CN1745049A

CN1745049A - Ligands for metals and improved metal-catalyzed processes based thereon

Info

Publication number: CN1745049A
Application number: CN 200380109502
Authority: CN
Inventors: S·L·布赫瓦尔德; X·黄; D·齐姆
Original assignee: Massachusetts Institute of Technology
Current assignee: Massachusetts Institute of Technology
Priority date: 2002-12-09
Filing date: 2003-12-09
Publication date: 2006-03-08
Anticipated expiration: 2023-12-09
Also published as: CN100548948C

Abstract

One aspect of the present invention relates to ligands for transition metals. A second aspect of the present invention relates to the use of catalysts comprising these ligands in transition metal-catalyzed carbon-heteroatom and carbon-carbon bond-forming reactions. The subject methods provide improvements in many features of the transition metal-catalyzed reactions, including the range of suitable substrates, reaction conditions, and efficiency.

Description

Metal ligands and improved metal catalytic processes based thereon

Government funding

The present invention was made with the support of grant number 9421982-CHE, granted by the national science foundation, and the U.S. government therefore has some rights in the invention.

Background

Transition metal catalyst complexes play an important role in many areas of chemistry including the preparation of polymers and pharmaceuticals. It is recognized that the properties of these catalyst complexes are affected by both the properties of the metal and the properties of the ligand bound to the metal atom. For example, the structural properties of the ligand can affect reaction speed, regioselectivity, and stereoselectivity. It is expected that large ligands will slow down the reaction rate; it is expected that in the coupling reaction, electron-withdrawing ligands can slow the oxidative addition to the metal center and accelerate the reductive elimination from the metal center; conversely, it is expected that in the coupling reaction, the multiple electron ligands will accelerate oxidative addition to the metal center and slow reductive elimination from the metal center.

In many cases, it is believed that the oxidative addition step in the accepted principles of the coupling reaction is rate limited. Thus, adjusting the overall catalytic system to increase the rate of the oxidative addition step can increase the overall reaction rate. In addition, it is known that the rate of oxidative addition of the transition metal catalyst to the carbon-halogen bond of the aryl halide decreases with the change from iodide to bromide to chloride, all other factorsbeing equal. Due to this fact, those members of the group consisting of active organic halide-chloride-which are more stable, lower molecular weight and certainly more readily available, are the worst substrates for conventional transition metal catalyzed coupling reactions and similar reactions.

To date, the best halogen-containing substrates for transition metal catalyzed carbon-heteroatom and carbon-carbon bond formation reactions have been iodides. Bromides are often acceptable substrates, but generally require higher temperatures, longer reaction times, and lower yields of the resulting product.

Summary of The Invention

One aspect of the present invention relates to novel transition metal ligands. A second aspect of the invention relates to the use of catalysts comprising these ligands in different transition metal catalyzed carbon-heteroatom and carbon-carbon bond forming reactions. The method provides improvements in many characteristics of transition-metal-catalyzed reactions, including suitable substrate range, number of catalyst turnovers, reaction conditions, and efficiency.

More specifically, unexpected and inventive improvements to transition metal catalyzed aryl amination reactions, aryl amidation reactions, Suzuki coupling to give biaryl products, and α -arylation of ketones have been achieved, for example, the use of alcohols such as t-butanol as solvents in certain processes of the invention allows the use of substrates containing those functional groups that were previously excluded because these functional groups do not have sufficient stability to survive the reaction conditions or because they in turn interfere with transition metal catalysis methods.

In another aspect, the ligands and methods of the invention can allow the first time conversion with aryl bromide or chloride to be efficiently performed at room temperature. In addition, the ligands and methods of the present invention allow the above-mentioned reactions to be carried out at a synthetically efficient rate, using very little catalyst, e.g., 0.000001 mol% relative to the limiting reagent.

Brief description of the drawings

FIG. 1 shows the preparation method and the reaction for screening various ligands.

FIG. 2 shows various embodiments of the present invention for forming carbon-nitrogen bonds using various ligands and various benzenesulfonates.

FIG. 3 shows various embodiments of the present invention for forming carbon-nitrogen bonds using various ligands and various benzenesulfonates.

FIG. 4 shows various embodiments of a carbon-nitrogen bond formation process and a carbon-carbon bond formation process using the preferred ligands of the invention and various aryl chlorides.

FIG. 5 shows various embodiments of carbon-carbon bond formation methods using the preferred ligands of the invention and various aryl chlorides.

FIG. 6 shows the results of the carbon-oxygen bond formation method of the present invention, depending on the ligand used in the present invention.

FIG. 7 shows the results of the carbon-oxygen bond formation method of the present invention, depending on the ligand used in the present invention.

FIG. 8 shows a synthetic scheme for the preparation of ligands of the invention.

FIG. 9 shows various embodiments of the carbon-nitrogen bond formation process of the present invention using the preferred ligands of the present invention and 4-butylphenyl chloride, depending on the base used.

FIG. 10 shows various embodiments of the carbon-nitrogen bond formation process of the present invention using the preferred ligands of the present invention and 4-butylphenyl chloride, depending on the base used.

FIG. 11 shows various embodiments of the carbon-nitrogen bond formation process of the present invention using the preferred ligands of the present invention and 4-butylphenyl chloride, depending on the amount of water in the reaction mixture.

FIG. 12 shows various embodiments of the carbon-nitrogen bond formation process of the present invention using the preferred ligands of the present invention and various aryl chlorides with varying amounts of water in the reaction mixture.

FIG. 13 shows various embodiments of the process for forming a carbon-nitrogen bond of the present invention using the preferred ligands of the present invention and 4-butylphenyl chloride as a function of reaction time

FIG. 14 shows various embodiments of the carbon-carbon bond forming process of the present invention using a plurality of (2 ', 4 ', 6 ' -triisopropylbiphenyl) di (alkyl) phosphines as palladium ligands, 4-tert-butylphenyl tosylate and phenylboronic acid. See example 66.

FIG. 15 shows various embodiments of the carbon-carbon bond forming process of the present invention using (2 ', 4 ', 6 ' -triisopropylbiphenyl) dicyclohexylphosphine as a palladium ligand, a plurality of aryl tosylates, and a plurality of aryl boronic acids. See example 66 and figure 14.

FIG. 16 shows various embodiments of the carbon-carbon bond forming process of the present invention using (2 ', 4 ', 6 ' -triisopropylbiphenyl) dicyclohexylphosphine as a palladium ligand, a plurality of aryl tosylates, and a plurality of aryl boronic acids. See example 66 and figure 14.

FIG. 17 shows various embodiments of the carbon-carbon bond forming process of the present invention using (2 ', 4 ', 6 ' -triisopropylbiphenyl) dicyclohexylphosphine as a palladium ligand, a plurality of aryl tosylates, and a plurality of aryl boronic acids. See example 66 and figure 14.

FIG. 18 shows various embodiments of the carbon-carbon bond forming methods of the present invention using a plurality of (2 ', 4 ', 6 ' -triisopropylbiphenyl) di (alkyl) phosphines as palladium ligands, a plurality of aryl tosylates, and a plurality of aryl boronic acids. See example 66 and figure 14.

FIG. 19 shows various embodiments of the carbon-carbon bond forming process of the present invention using (2 ', 4 ', 6 ' -triisopropylbiphenyl) dicyclohexylphosphine as a palladium ligand, a plurality of aryl tosylates, and a plurality of aryl boronic acids. See example 66 and figure 14.

Detailed description of the invention

Ligands of the invention

In some embodiments, the ligands of the invention are represented by structure I:

wherein

For each occurrence, R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl and- (CH)₂)_m-R₈₀；

The A and A' rings of the biphenyl center may be independently unsubstituted or each independently represented by R₁And R₂Substitution, any maximum number of substitutions is defined by the rules of stability and valency.

When present,R for each case₁And R₂Independently selected from alkyl, cycloalkaneRadical, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -SiR₃And- (CH)₂)_m-R₈₀；

R₈₀Represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclic;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the ligands of the present invention are represented by structure I and the attendant definitions, wherein for each occurrence R independently represents alkyl, cycloalkyl, or aryl; at least two kinds of R exist₂Examples of (1); for each case, R₂Independently selected from alkyl and cycloalkyl.

In some embodiments, the ligands of the invention are represented by structure II:

wherein

For each occurrence, R and R' are independently selected from the group consisting of alkyl, cycloalkyl and- (CH)₂)_m-R₈₀；

When present, R for each case₁And R₂Independently selected from alkyl, cycloalkyl, halogen, -SiR₃And- (CH)₂)_m-R₈₀；

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein for each occurrence R independently represents alkyl or cycloalkyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein for each occurrence R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein for each occurrence R independently represents cyclohexyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein for each occurrence R' independently represents alkyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein for each occurrence R' independently represents isopropyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents an alkyl or cycloalkyl group.

In some embodiments, the ligands of the present invention are represented by structureII and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents alkyl or cycloalkyl; and for each occurrence, R' independently represents an alkyl group.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl; and for each occurrence, R'Independently represents an alkyl group.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl; and for each occurrence, R' independently represents an alkyl group.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents alkyl or cycloalkyl; and for each occurrence, R' independently represents isopropyl.

In some embodiments, the ligands of the present invention are represented by structure IIand the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl; and for each occurrence, R' independently represents isopropyl.

In some embodiments, the ligands of the present invention are represented by structure II and the attendant definitions, wherein R is₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl; and for each occurrence, R' independently represents isopropyl.

Method of the invention

In some embodiments, the methods of the invention are represented by scheme 5:

scheme 5

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

r 'and R' are independently selected for each occurrence from H, alkyl, heteroalkyl, aryl, formyl, acyl, alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl;

r' and R "together may form an optionally substituted ring consisting of 3 to 10 backbone atoms; said ring optionally containing one or more heteroatoms other than the nitrogen to which R 'and R' are attached;

r 'and/or R' may be covalently bound to Z;

the transition metal is selected from group 10 metals;

the base is selected from the group consisting of fluoride, hydride, hydroxide, carbonate, phosphate, alkoxide, metal amide, and carbanion; and

the ligand is selected from:

a compound represented by I:

wherein

When present, R for each case₁And R₂Independently selected from alkyl, cycloalkyl, heterocycleAlkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -SiR₃And- (CH)₂)_m-R₈₀；

R₈₀Represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer; and

a compound represented by II:

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the methods related to the present invention are represented by scheme 1 and the attendant definitions, wherein the transition metal is palladium.

In some embodiments, the methods of the invention are represented by scheme 6:

scheme 6

Wherein

Z and Ar' are independently selected from optionally substituted aryl, heteroaryl and alkenyl

X is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

z and Ar' may be covalently linked;

the transition metal is selected from group 10 metals;

the ligand is selected from:

a compound represented by I:

wherein

When present, R for each case₁And R₂Independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -SiR₃And- (CH)₂)_m-R₈₀；

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer; and a compound represented by II:

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the present invention relates to the process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein X is-OS (O)₂And (4) an aryl group.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein X is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein X is-OS (O)₂Tolyl radicals.

In some embodiments, the present invention relates to the method represented by scheme 6 and the attendant definitions, wherein said base is selected from the group consisting of fluoride, carbonate, and phosphate.

In some embodiments, the present invention relates to the method represented by scheme 6 and the attendant definitions, wherein said base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; and X is-OS (O)₂And (4) an aryl group.

In some embodiments, the presentinvention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; and X is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; and X is-OS (O)₂Tolyl radicals.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; x is-OS (O)₂An aryl group; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; x is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; x is-OS (O)₂Tolyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; x is-OS (O)₂An aryl group; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the attendant definitions, wherein the transition metal is palladium; x is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group;and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to a process represented by scheme 6 and the definitions attached hereto, whichWherein the transition metal is palladium; x is-OS (O)₂Tolyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the methods of the invention are represented by scheme 7:

scheme 7

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

r is selected from the group consisting of H, alkyl, heteroalkyl, aralkyl, aryl, heteroaryl, alkoxy, alkylthio, alkylamino, and arylamino;

r' is selected from the group consisting of H, alkyl, heteroalkyl, aralkyl, aryl, heteroaryl, formyl, acyl, alkoxycarbonyl, alkylaminocarbonyl, and arylaminocarbonyl;

r' is selected from the group consisting of H, alkyl, heteroalkyl, aralkyl, aryl and heteroaryl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

one of Z and R, R', R "may be covalently linked;

the transition metal is selected from group 10 metals;

the ligand is selected from:

a compound represented by I:

wherein

The A and A' rings of the biphenyl center may independently be unsubstitutedSubstituted or each independently of R₁And R₂Substitution, any maximum number of substitutions is defined by the rules of stability and valency.

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the present invention relates to a process represented by scheme 7 and the attendant definitions, wherein the transition metal is palladium.

In some embodiments, the methods of the invention are represented by scheme 8:

scheme 8

Wherein

Z and Ar' are independently selected from optionally substituted aryl, heteroaryl and alkenyl;

ar' is selected from optionally substituted aromatic moieties;

z and Ar' may be covalently linked;

the catalyst consists essentially of at least one palladium atom or ion and at least one ligand;

the ligand is selected from:

a compound represented by I:

wherein

For each occurrence, R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and mixtures thereof,Aralkyl, heteroaralkyl and- (CH)₂)_m-R₈₀；

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the present invention relates to methods represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl or phenyl.

In some embodiments, the present invention relates to processes represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl.

In some embodiments, the present invention relates to a method represented by scheme 8 and the attendant definitions, wherein said base is selected from the group consisting of fluoride, carbonate, and phosphate.

In some embodiments, the present invention relates to the method represented by scheme 8 and the attendant definitions, wherein said base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to methods represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl or phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to methods represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl or phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to processes represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to processes represented by scheme 8 and the attendant definitions, wherein Ar "is tolyl; andthe base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the methods of the invention are represented by scheme 9:

scheme 9

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

ar' is selected from optionally substituted aromatic moieties;

one of Z and R, R', R "may be covalently linked;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is tolyl or phenyl.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is phenyl.

In some embodiments, the present invention relates to the method represented by scheme 9 and the attendant definitions, wherein said base is selected from the group consisting of fluoride, carbonate, and phosphate.

In some embodiments, the present invention relates to the method represented by scheme 9 and the attendant definitions, wherein said base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is tolyl or phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is tolyl or phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to methods represented by scheme 9 and the attendant definitions, wherein Ar "is phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the methods of the invention are represented by scheme 10:

scheme 10

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

for each occurrence, R and R' are independently selected from H, alkyl, heteroalkyl, aryl, formyl, acyl, alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl;

r' and R "together may form an optionally substituted ring containing 3 to 10 backbone atoms; said ring optionally containing one or more heteroatoms other than the nitrogen atom to which R 'and R' are attached;

r' and/or R "may be covalently linked to Z;

the solvent is water;

the base is selected from the group consisting of fluoride, hydroxide, carbonate, phosphate, and alkoxide; and

the ligand is selected from the group consisting of compounds represented by I:

wherein

When present, R for each case₁And R₂Is independently selected fromAlkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, -SiR₃And- (CH)₂)_m-R₈₀；

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and, when chiral, the ligand is a mixture ofenantiomers or a single enantiomer.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein the base is selected from the group consisting of carbonate and hydroxide.

In some embodiments, the present invention relates to the process represented by scheme 10 and the attendant definitions, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein the base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein X is Cl, Br or I.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein X is Cl or Br.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein X is Cl.

In some embodiments, the present invention relates to methods represented by scheme 10 and the attendant definitions, wherein Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; and X is Cl, Br or I.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; x is Cl, Br or I; and Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; x is Cl or Br.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; x is Cl or Br; and Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; x is Cl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of carbonate and hydroxide; x is Cl; and Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl, Br or I; and Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl or Br; and Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 10 and the attendant definitions, wherein said base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl; and Z is optionally substituted phenyl.

In some embodiments, the methods of the invention are represented by scheme 11:

scheme 11

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

for each occurrence, R 'and R' are independently selected from H, alkyl, heteroalkyl, aryl, formyl, acyl, alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl;

r' and/or R "may be covalently linked to Z;

the solvent comprises greater than 50% by volume of a hydroxylic solvent;

the ligand is selected from the group consisting of compounds represented by I:

wherein

For each occurrence, R is independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, and mixtures thereof,Aralkyl, heteroaralkyl and- (CH)₂)_m-R₈₀；

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and, when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is a lower alkyl alcohol.

In some embodiments, the present invention relates to the process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is t-butyl alcohol.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein said solvent consists essentially of said hydroxylic solvent.

In some embodiments, the present invention relates to the process represented by scheme 11 and the attendant definitions, wherein the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides.

In some embodiments, the present invention relates to the process represented by scheme 11 and the attendant definitions, wherein the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein X is Cl or Br.

In some embodiments, the present invention relates to methods represented by scheme 11 and the attendant definitions, wherein Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 11 and theattendant definitions, wherein the hydroxylic solvent is a lower alkyl alcohol; and the solvent consists essentially of the hydroxylic solvent.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is t-butanol; and the solvent consists essentially of the hydroxylic solvent.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides; and X is Cl or Br.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides; x is Cl or Br. And Z is optionally substituted phenyl.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and X is Cl or Br.

In some embodiments, the present invention relates to a process represented by scheme 11 and the attendant definitions, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; x is Cl or Br; and Z is optionally substituted phenyl.

In some embodiments, the methods of the invention are represented by scheme 12:

scheme 12

Wherein

Z is selected from optionally substituted monocyclic and polycyclic aromatic and heteroaromatic moieties;

ar' is selected from optionally substituted aromatic moieties;

r is selected from optionally substituted alkyl and aralkyl;

for each occurrence, R' is independently selected from alkyl and heteroalkyl; the alkyl and heteroThe carbon-boron bond of the alkyl group is inert under the reaction conditions; b (R')₂Together may represent 9-borabicyclo [3.3.1]Nonyl radical.

Z and R may be covalently linked;

the ligand is selected from the group consisting of compounds represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

In some embodiments, the present invention relates to methods represented by scheme 12 and the attendant definitions, wherein Ar "is tolyl or phenyl.

In some embodiments, the present invention relates to a method represented by scheme 12 and the attendant definitions, wherein said base is selected from the group consisting of fluoride, carbonate, and phosphate.

In some embodiments, the present invention relates to a method represented by scheme 12 and the attendant definitions, wherein the base is cesium fluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

In some embodiments, the present inventionThe invention relates to a process represented by scheme 12 and the attendant definitions, wherein B (R')₂Together may represent 9-borabicyclo [3.3.1]Nonyl radical.

In some embodiments, the present invention relates to methods represented by scheme 12 and the attendant definitions, wherein Ar "is tolyl or phenyl; the base is selected from the group consisting of fluoride, carbonate and phosphate.

In some embodiments, the present invention relates to methods represented by scheme 12 and the attendant definitions, wherein Ar "is tolyl or phenyl; the base is selected from cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

In some embodiments, the present invention relates to methods represented by scheme 12 and the attendant definitions, wherein Ar "is tolyl or phenyl; the base is selected from fluoride, carbonate and phosphate; and B (R')₂Together represent 9-borabicyclo [3.3.1]Nonyl radical.

In some embodiments, the present invention relates to methods represented by scheme 12 and the attendant definitions, wherein Ar "is tolyl or phenyl; the base is selected from cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate; and B (R')₂Together represent 9-borabicyclo [3.3.1]Nonyl radical.

In some embodiments, the methods of the invention are represented by scheme 13:

scheme 13

Wherein

Ar is selected from optionally substituted monocyclic and polycyclic aromatic and heteroaromatic moieties;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

for each occurrence, R and R' are independently selected from H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl;

r 'and/or R' may be covalently linked to Ar;

the transition metal is selected from the group consisting of metals of groups 8-10;

the base is selected from the group consisting of hydrides, hydroxides, carbonates, phosphates, alkoxides, amides, carbanions, and silyl anions; and

the ligand is selected from the group consisting of compounds represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and the number of the first and second groups,

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

In some embodiments, the methods of the invention are represented by scheme 14:

scheme 14

Wherein

Ar and Ar' are independently selected from optionally substituted monocyclic and polycyclic aromatic and heteroaromatic moieties;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

ar and Ar' may be covalently linked;

the ligand is selected from the group consisting of compounds represented by I:

wherein

For each occurrence, R is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkylAnd- (CH)₂)_m-R₈₀；

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

In some embodiments, the methods of the invention are represented by scheme 15:

scheme 15

Wherein

r is selected from optionally substituted alkyl, heteroalkyl, and aralkyl;

for each occurrence, R' is independently selected from alkyl and heteroalkyl; the carbon-boron bond of the alkyl and heteroalkyl groups is inert under reaction conditions; BR'₂Together may represent 9-borabicyclo [3.3.1]Nonyl radical.

X is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

ar and R may be covalently linked;

the base is selected from the group consisting of hydrides, hydroxides, carbonates, phosphates, alkoxides,amides, carbanions, and silyl anions; and

the ligand is selected from the group consisting of compounds represented by I:

wherein

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

In some embodiments, the methods of the invention are represented by scheme 16:

scheme 16

Wherein

for each occurrence R, R' and R "are independently selected from H, alkyl, heteroalkyl, aralkyl, aryl, heteroaryl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

one of Ar and R, R' and R "may be covalently linked;

the ligand is selected from the group consisting of compounds represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and, when chiral, the ligand is a mixture of enantiomers or a single enantiomer; and a compound represented by II:

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

In some embodiments, the present invention relates to a process represented by any of the above schemes, which provides a product in a yield of greater than 50%; in a more preferred embodiment, the product is provided in a yield of greater than 70%; and in the most preferred embodiment provides a product yield of greater than 85%.

In some embodiments, the invention relates to a method represented by any of the above schemes, wherein the transition metal and ligand are selected to provide the product at room temperature.

In some embodiments, the present invention relates to a method represented by any of the above schemes, wherein the transition metal and ligand are selected so as to provide a product when X is chloride.

In some embodiments, the present invention relates to a process represented by any of the above schemes, wherein the transition metal and ligand are selected so as to provide a product using less than 0.01 mol% of catalyst relative to the defined reagent.

In some embodiments, the invention relates to a process represented by any of the above schemes, wherein the transition metal and ligand are selected so as to provide a product using less than 0.0001 mol% of catalyst relative to the defined reagent.

In some embodiments, the present invention relates to a method represented by any of the above schemes, wherein the transition metal and ligand are selected so as to consume the defined agent in less than 48 hours.

In some embodiments, the present invention relates to a method represented by any of the above schemes, wherein the transition metal and ligand are selected so as to consume the defined agent in less than 24 hours.

In some embodiments, the present invention relates to a method represented by any of the above schemes, wherein the transition metal and ligand are selected so as to consume the defined agent in less than 12 hours.

Various general studies

For example, in the amination reaction of the present invention, the amine may be present in only a twofold excess relative to the aromatic compound and preferably in no more than 20% excess.

The reaction generally takes place at mild temperatures and pressures to give high yields of the products arylamines, biaryls, α -aryl ketones and the like, thus, according to the present invention, yields of the desired products of greater than 45%, preferably greater than 75%, and more preferably greater than 80% can be obtained at mild temperatures.

The reaction can be carried out in a wide range of solvent systems including polar aprotic solvents. Alternatively, in some embodiments, the reaction may be carried out in the absence of an additional solvent.

It is possible to provide synthetic schemes for arylamines, biaryls, α -aryl ketones and the like, which can be carried out under mild conditions and/or in non-polar solvents, which have a wide range of uses, in particular in the agricultural and pharmaceutical industries, and in the polymerization industry.

Thus, another aspect of the invention relates to the use of such methods to generate libraries of different compounds, such as arylamines, biaryls, α -aryl ketones, and the like, as well as to libraries of compounds per se.

The ligands and methods of the present invention are capable of forming carbon-heteroatom and carbon-carbon bonds by transition metal catalyzed amination, Suzuki coupling, α -arylation of carbonyl groups, etc., under conditions where the appropriate amount of the product is not obtained using ligands and methods known in the art. in preferred embodiments, the ligands and methods of the present invention catalyze the above-described transformation at temperatures below 50 ℃ and in some embodiments the transformation occurs at room temperature.

The ligands of the invention and the methods based thereon can be used to produce synthetic intermediates which are converted to the desired end products, such as lead compounds in medicinal chemical procedures, pharmaceuticals, pesticides, antivirals and fungicides, by other methods known in the art. In addition, the ligands of the invention and the methods based thereon may be used to increase the efficiency of known methods and/or shorten known routes to desired end products, such as lead compounds in medicinal chemical procedures, drugs, pesticides, antivirals and fungicides.

Definition of

For convenience, before further description of the invention, certain terms used in the specification, examples, and appended claims are explained herein.

The terms "biphenyl" and "binaphthyl" denote the following ring systems. The numbers surrounding the ring system are the position numbering system used herein. Also, capital letters among each ring of the ring system are ring descriptors as used herein.

Biphenyl binaphthyl group

The term "substituted aryl" denotes an aryl group containing an electrophilic atom which is susceptibleto the cross-linking coupling reaction, e.g. the electrophilic atom carries a leaving group. In reaction scheme 1, the substrate aryl is represented by ArX, X being a leaving group. The aryl group, Ar, if substituted, is substituted at other positions than X. The substrate aryl group may be a single ring molecule, or may be a macromolecular moiety.

The term "nucleophile" is known in the art and as used herein means a chemical moiety having a reactive pair of electrons.

The term "electrophile" is known in the art and denotes a chemical moiety that can accept an electron pair from a nucleophile as defined above. Electrophile moieties useful in the methods of the invention include halides and sulfonates.

The terms "electrophilic atom", "electrophilic center" and "reactive center" as used herein refer to an atom of the aryl moiety of the substrate that is attacked and forms a new bond to a nucleophilic heteroatom such as hydrazine. In most (but not all) cases, it may also be an aromatic ring atom from which the leaving group is detached.

The term "electron withdrawing group" is known in the art and denotes the tendency of a substituent to draw a valence electron from a neighboring atom, i.e., the substituent is electronegative relative to the neighboring atom. The level of quantified electron withdrawing ability is given by the Hammett σ(s) constant. Such well-known constants are described in a number of references such as J.March, Advanced Organic Chemistry, McGraw Hill Book company, New York, (1977 edition) p.251-259. The Hammett constant value is generally negative for electron donating groups (for NH₂，s[P]-0.66) and positive for an electron withdrawing group (for nitro, s [ P)]＝0.78)，s[P]Represents para substitution. Examples of electron withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chlorine, andthe like. Examples of electron donating groups include amino, methoxy, and the like.

The term "reaction product" denotes a compound resulting from the reaction of hydrazine or the like with the substrate aryl group. Generally, the term "reaction product" as used herein denotes stable, isolatable aryl ether adducts and does not relate to unstable intermediates or transition states.

The term "catalytic amount" is known in the art and denotes a sub-stoichiometric amount of a reagent relative to the reactants. As used herein, catalytic amounts refer to 0.0001 to 90 mole% of the reagent relative to the reactants, more preferably 0.001 to 50 mole% of the reagent relative to the reactants, still more preferably 0.01 to 10 mole%, even more preferably from 0.1 to 5 mole%.

The term "alkyl" denotes saturated aliphatic groups including straight chain alkyl, branched chain alkyl, cycloalkyl (alicyclic), alkyl substituted cycloalkyl, cycloalkyl substituted alkyl. In a preferred embodiment, the linear or branched alkyl group has 30 or less carbon atoms (e.g., C) in its backbone₁-C₃₀Straight chain, C₃-C₃₀Branched), more preferably 20 or less carbon atoms. Likewise, preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, more preferably 5, 6 or 7 carbon atoms in the ring structure.

In addition, the term "alkyl" (or "lower alkyl") as used throughout the specification and claims is meant to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which means that the alkyl moiety has a substituent that replaces a hydrogen on one or more carbon atoms of the hydrocarbon backbone. The substituents may include, for example, halogen, hydroxy, carbonyl (e.g., carboxy, ester, formyl, or ketone), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphonic acidEster, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that the substituted moiety on the hydrocarbon chain may itself be substituted, if appropriate. For example, the substituents of a substituted alkyl group can include substituted and unsubstituted forms of the following groups: amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), silyl, and ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate and ester), -CF₃CN, -CN, etc. Typical substituted alkyl groups are illustrated below. Cycloalkyl groups may be alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF₃and-CN, etc.

The term "aralkyl" as used herein, denotes an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" denote unsaturated aliphatic groups of similar length and possible substitution for the alkyl groups described above, but which contain at least one double or triple bond, respectively.

"lower alkyl" as used herein means an alkyl group as defined above, but having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, in its backbone structure, except that the number of carbons is otherwise defined. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyl groups. In a preferred embodiment, the substituents for alkyl groups specified herein are lower alkyl groups.

The term "aryl" as used herein includes 5-, 6-and 7-membered monocyclic aromatic groups, which may include 0-4 heteroatoms, such as benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. These aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring may be substituted at one or more ring positions with substituents described above, such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF₃CN, -CN, etc. Operation of the artThe term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjoining rings (the rings are "fused rings"), wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms and dba denote methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl and dibenzylideneacetone, respectively. A more comprehensive list of abbreviations used by those of ordinary skill in the art of Organic Chemistry may be found in the first phase of each volume of the Journal of Organic Chemistry; the tables typically appear as Standard List of Abbrelations tables. The abbreviations in the tables and all abbreviations used by those of ordinary skill in the art of organic chemistry are incorporated herein by reference.

The terms ortho, meta and para are used to denote 1, 2-, 1, 3-and 1, 4-disubstituted benzenes, respectively. For example, 1, 2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The term "heterocyclyl" or "heterocyclic group" denotes a 3-to 10-membered ring structure, more preferably a 3-to 7-membered ring, which ring structure includes 1-4 heteroatoms the heterocycle may also be polycyclic heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, benzopyran, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, 2, 3-naphthyridine, 1, 5-naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane (oxolane), thiolane (thiolane), oxazole, piperidine, piperazine, morpholine, lactones, lactams such as β -propiolactones and pyrrolidones, sulfonamides, aryl amides, substituted at one or more positions with, for example, halogen, sulfenyl, aryl₃CN, -CN, etc.

The term "polycyclyl" or "polycyclic group" refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbon atoms are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are connected by non-adjacent atoms are referred to as "bridged" rings. Each ring of the polycycle can be substituted with such substituents as defined above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, and the like,Ketones, aldehydes, esters, heterocyclic groups, aromatic or heteroaromatic moieties, -CF₃CN, -CN, etc.

The term "carbocyclic" as used herein denotes an aromatic or non-aromatic ring wherein each atom of the ring is carbon.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.

The term "nitro" as used herein means-NO₂(ii) a The term "halogen" denotes-F, -Cl, -Br or-I; the term "sulfhydryl" denotes-SH; the term "hydroxy" denotes-OH; and the term "sulfonyl" denotes-SO₂-。

The terms "amine" and "amino" are known in the art and represent unsubstituted and substituted amines, such as moieties that can be represented by the general formula:

or

Wherein R is₉、R₁₀And R'₁₀Each independently represents hydrogen, alkyl, alkenyl, - (CH)₂)_m-R₈Or R₉And R₁₀Together with the N atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms in the ring structure; r₈Represents aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is 0 or an integer in the range of 1 to 8. In a preferred embodiment, there is only one R₉Or R₁₀May be a carbonyl group, e.g. R₉、R₁₀Together with the nitrogen atom, cannot form an imide. In a more preferred embodiment, R₉And R₁₀(and optionally R'₁₀) Each independently represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R₈. Thus, the term "alkylamine" as used herein denotes an amine group as defined above having a substituted or unsubstituted alkyl group attached thereto, i.e., R₉And R₁₀At least one of which is an alkyl group.

The term "acylamino" is known in the art and denotes a moiety which may be represented by the general formula:

wherein R is₉R 'as defined above'₁₁Represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R₈Wherein m and R₈As defined above.

The term "amido" is known in the art as an amino-substituted carbonyl and includes moieties that can be represented by the general formula:

wherein R is₉、R₁₀As defined above. Preferred embodiments of the amides will not include imides, which are unstable.

The term "alkylthio" denotes an alkyl group as defined above having a sulfur attached thereto. In a preferred embodiment, the "alkylthio" moiety consists of-S-alkyl, -S-alkenyl, -S-alkynyl and-S- (CH)₂)_m-R₈One of them represents, wherein m and R₈As defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

The term "carbonyl" is known in the art and includes moieties that can be represented by the general formula:

or

Wherein X is a bond or represents oxygen or sulphur, and R₁₁Represents hydrogen, alkyl, alkenyl, - (CH)₂)_m-R₈Or a pharmaceutically acceptable salt, R'₁₁Represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R₈Wherein m and R₈As defined above. When X is oxygen and R₁₁Or R'₁₁When not hydrogen, the formula represents an "ester". When X is oxygen, R₁₁As defined above, referred to herein are carboxy moieties, particularly when R₁₁Is hydrogenWhen said formula represents a "carboxylic acid". When X is oxygen, and R'₁₁When hydrogen, the formula represents a "formate". Typically, when the oxygen atom of the above formula is replaced by thio, said formula represents a "thiocarbonyl". When X is sulfur and R₁₁Or R'₁₁When not hydrogen, the formula represents "sulfurAcid esters ". When X is sulfur and R₁₁When hydrogen, the formula represents a "thiocarboxylic acid". When X is sulfur and R'₁₁When hydrogen, the formula represents a "thioformate". On the other hand, when X is a bond and R₁₁When not hydrogen, the above formula represents a "ketone" group. When X is a bond and R₁₁When hydrogen, the above formula represents an "aldehyde" group.

The term "alkoxy group" or "alkoxy" as used herein is an alkyl group, as defined above, having an oxy group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like. An "ether" is a covalent linkage of two hydrocarbons by one oxygen. Correspondingly, substituents of alkyl groups, which render the alkyl group as an ether, are or are analogous to alkoxy groups, which may be substituted, for example, by-O-alkyl, -O-alkenyl, -O-alkynyl, -O- (CH)₂)_m-R₈One of them represents, wherein m and R₈As defined above.

The term "sulfonate" is known in the art and includes moieties that can be represented by the general formula:

wherein R is₄₁Is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

The terms triflyl, tosyl, mesyl and nonaflonyl are known in the art and denote trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl and nonafluorobutanesulfonyl, respectively. The terms triflate, tosylate, mesylate and nonaflatate are known in the art and denote triflate, p-tosylate, mesylate and nonafluorobutanesulfonate functional groups, respectively, and molecules containing such groups, respectively.

The term "sulfate" is known in the art and includes moieties that can be represented by the general formula:

wherein R is₄₁As defined above.

The term "sulfonamido" is known in the art and includes moieties that can be represented by the general formula:

wherein R is₉And R'₁₁As defined above.

The term "sulfamoyl" is known in the art and includes moieties that can be represented by the following general formula:

wherein R is₉And R₁₀As defined above.

The term "sulfoxide" or "sulfinyl" as used herein is meant to include moieties which may be represented by the general formula:

wherein R is₄₄Selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl or aryl.

"phosphoryl" may be generally represented by the formula:

wherein Q₁Represents S or O, R₄₆Represents hydrogen, lower alkyl or aryl.

When used to substitute, for example, an alkyl group, the phosphoryl group of a phosphoryl alkyl group may be represented by the general formula:

or

Wherein Q₁Represents S or O, each R₄₆Independently represent hydrogen, lower alkyl or aryl, Q₂Represents O, S or N. When Q is₁When S, the phosphoryl moiety is a "thiophosphonate".

"Phospharamidate" can be represented by the following general formula:

or

Wherein R is₉And R₁₀As defined above, Q₂Represents O, S or N.

"phosphonamidate" can be represented by the following general formula:

or

Wherein R is₉And R₁₀As defined above, Q₂Represents O, S or N, and R₄₈Represents lower alkyl or aryl, Q₂Represents O, S or N.

"selenoalkyl" means an alkyl group having a substituted seleno group attached thereto. Representative "selenoethers", which may be substituted on the alkyl group, are selected from the group consisting of-Se-alkyl, -Se-alkenyl, -Se-alkynyl and-Se- (CH)₂)_m-R₈One of, m and R₈As defined above.

Similar substitutions may bemade to alkenyl and alkynyl groups to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups.

The phrase "protecting group" as used herein means a temporary variant of a group having a potentially reactive functional group that protects the group from unwanted chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl esters of alcohols, acetals and ketals of aldehydes and ketones, respectively. An overview of the chemistry of protecting Groups has been given (Greene, T.W.; Wuts, P.G.M.protective Groups in Organic Synthesis, second edition; Wiley: New York, 1991).

It is understood that "substituted" or "substituted" includes the implied condition that the substitution is in accordance with the valency allowed by the atom and substituent being substituted, and that the substitution reaction results in a stable compound that, for example, cannot spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like.

As used herein, the term "substituted" is intended to include all possible substituents of the organic compound. In a broad aspect, possible substituents include those of acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. Illustrative substituents include, for example, those described above. Possible substituents may be one or more identical or different substituents for suitable organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any of the possible substituents of the organic compounds described herein which correspond to the valency of the heteroatom. The present invention is not limited in any way by the possible substituents of the organic compounds.

"polar solvent" means a solvent having a dielectric constant (. epsilon.) of 2.9 or more, such as DMF, THF, ethylene glycol dimethyl ether (DMF), DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether. Preferred polar solvents are DMF, DME, NMP and acetonitrile.

By "aprotic solvent" is meant a non-nucleophilic solvent having a boiling point range above room temperature at atmospheric pressure, preferably from about 25 ℃ to about 190 ℃, more preferably from about 80 ℃ to about 160 ℃, and most preferably from about 80 ℃ to about 150 ℃ at atmospheric pressure. Examples of such solvents include acetonitrile, toluene, DMF, diglyme, THF or DMSO.

By "polar, aprotic solvent" is meant a solvent as defined above which does not have hydrogen available for exchange with the compound of the invention in the reaction, for example DMF, acetonitrile, diglyme, DMSO or THF.

For the purposes of the present invention, the chemical elements are identified according to the periodic Table of the elements, CAS version, an internal applied handbook of chemistry and Physics, 67 th edition 1986-87. Also for the purposes of the present invention, the term "hydrocarbon" is intended to include all possible compounds having at least one hydrogen and one carbon atom. In a broad aspect, possible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds, which may be substituted or unsubstituted.

Typical catalytic reactions

As noted above, one of applicants' invention features a transition metal catalyzed amination reaction that includes combining an amine with a substrate aryl group having an activating group X. The reaction includes at least a catalytic amount of a transition metal catalyst comprising a novel ligand, the binding being carried out under suitable metal catalyst catalyzed arylation conditions of the amine.

The two ligands (24 and 25) shown below refer to the numbers in the embodiments illustrated in this section.

In an illustrative embodiment, the process can be used for an intermolecular reaction between a polyelectronic aryl chloride and pyrrolidine to give an N-arylpyrrolidine:

in a second illustrated embodiment, the method can be used to N-arylate indoles with a multi-electron aryl bromide:

another aspect of the invention relates to the catalysis of Pd/4 by amination of electron deficient aryl chlorides as shown by the conversions illustrated below.

Another aspect of the invention relates to room temperature amination of aryl iodides or bromides as shown below with respect to the illustrated conversion of aryl iodides.

In another illustrative embodiment, the process is utilized in the palladium-catalyzed amination of electrically neutral aryl chlorides.

One of ordinary skill in the art will be able to envision intermolecular variations of the amination process. The illustrated embodiments are as follows:

another aspect of the invention features a transition metal catalyzed Suzuki cross-coupling reaction between an arylboronic acid, arylboronic ester, alkylborane, or the like, and a substrate aryl group having a reactive group X. The reaction includes at least a catalytic amount of a transition metal catalyst containing a novel ligand, the binding being carried out under conditions suitable for the metal catalyst to catalyze a cross-coupling reaction between the boron-containing reactant and the substrate aryl reactant.

In an illustrative embodiment of the Suzuki coupling aspect of the invention, the process can be utilized in the preparation of 3, 5-dimethoxybiphenyl from 1-chloro-3, 5-dimethoxybenzene and phenylboronic acid at room temperature:

in a second illustrative embodiment of the Suzuki coupling aspect of the invention, it may be in sp²-sp³The method is utilized in carbon-carbon bond formation; reacting the multi-electron aryl chloride with alkyl borane to obtain alkyl aromatic hydrocarbon:

one of ordinary skill in the art would be able to envision intermolecular variants of the Suzuki coupling method. The illustrated embodiments are as follows:

a further aspect of the invention features α -arylation of a transition metal catalyzed ketone involving reaction of an enolizable ketone with a substrate aryl group having an active group X, the reaction including at least a catalytic amount of a transition metal catalyst containing a novel ligand, the combination being carried out under conditions suitable for the metal catalyst to catalyze the α -arylation of the enolizable ketone.

In an embodiment illustrating the α -arylation aspect of the invention, the process can be utilized in the preparation of 6-methyl-2- (3, 4-dimethylphenyl) cyclohexanone from 1-bromo-3, 4-dimethylbenzene and 2-methylcyclohexanone at room temperature:

one of ordinary skill in the art would be able to envision intermolecular variations of the α -arylation process.

The substrate aryl compounds include compounds derived from the following simple aromatic (monocyclic or polycyclic) or heteroaromatic (monocyclic or polycyclic) rings: such aromatic rings are, for example, benzene, naphthalene, anthracene and phenanthrene; examples of such heteroaromatic rings are pyrrole, thiophene, thianthrene, furan, pyran, isobenzofuran, benzopyran, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, thiazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, 2, 3-naphthyridine, 1, 5-naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, perimidine, phenanthroline, phenazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxalane, thiolane, oxazole, piperidine, piperazine, morpholine and the like. In preferred embodiments, the reactive group X is substituted on a 5-, 6-or 7-membered ring (although it may be part of a larger polycyclic ring).

In a preferred embodiment, the aryl substrate may be selected from phenyl and phenyl derivatives, heteroaromatics, polycyclic aromatics and heteroaromatics and functional derivatives thereof. Suitable aromatic compounds are derived from simple aromatic and heteroaromatic rings, including, but not limited to, pyridine, imidazole, quinoline, furan, pyrrole, thiophene, and the like. Suitable aromatic compounds are derived from fused ring systems including, but not limited to, naphthalene, anthracene, 1,2, 3, 4-tetrahydronaphthalene, indole, and the like.

Suitable aromatic compounds may have the formula Z_pArX, wherein X is a reactive substituent. The reactive substituent X is characterized as a good leaving group. Typically, the leaving group is, for example, a halide or sulfonate. Suitable reactive substituents include, by way of example only, halogens such as chlorine, bromine, and iodine, and sulfonates such as triflate, mesylate, nonafluorobutanesulfonate, and p-toluenesulfonate. In some embodiments, the leaving group is a halogen selected from iodine, bromine, and chlorine.

Z represents one or more substituents optionally on the aromatic ring, although each occurrence of Z (p>1) is independently selected. By way of example only, each substitution that occurs may be independently, where valency and stability permit, halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (e.g., ester, carboxylate, or formate), thiocarbonyl (e.g., thiol ester, thiocarboxylate, or monothioformate), carbonyl, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, - (CH), or₂)_m-R₈、-(CH₂)_m-OH、-(CH₂)_m-O-lower alkyl, - (CH)₂)_m-O-lower alkenyl, - (CH)₂)_m-O-(CH₂)_n-R₈、-(CH₂)_m-SH、-(CH₂)_m-S-lower alkyl, - (CH)₂)_m-S-lower alkenyl, - (CH)₂)_m-S-(CH₂)_n-R₈Or a protecting group or a solid or polymeric support as above; r₈Represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocycle; n and m are independently at each occurrence zero or an integer in the range of 1 to 6. P is preferably in the range of 0 to 5. For fused rings, P can be adjusted appropriately as the number of substitutions on the aryl group increases.

In some embodiments, suitable substituents Z include alkyl, aryl, acyl, heteroaryl, amino, carboxylate, carboxylic acid, hydrogen, ether, thioether, amide, carboxamide, nitro, phosphonic acid, hydroxyl, sulfonic acid, halide, pseudohalide groups and their substituted derivatives, and P is in the range of 0 to 5. In particular, the reaction is predicted to be adaptable to acetals, amides and silyl ethers. For fused rings, P can be adjusted appropriately as the number of substituents of the aromatic ring increases.

A variety of substrate aryl groups may be used in the methods of the invention. The choice of substrate will depend on factors such as the amine, boronic acid, ketone, etc. used and the desired product, and suitable aryl substrates should be apparent to those skilled in the art having the benefit of the teachings of this invention. It should be understood that the aryl substrate preferably does not contain any interfering functional groups. It should also be understood that not all active aryl substrates may be reacted with every amine, boronic acid, ketone, etc.

Reactive amines, boronic acids, ketones, and the like can be molecules separated from the substrate aryl, or substituents of the same molecule (e.g., for intramolecular variations).

The amines, boronic acids, ketones, and the like are selected to provide the desired reaction product. The amines, boronic acids, ketones, and the like may be functionalized. The amines, boronic acids, ketones, and the like can be selected from a variety of structural types including, but not limited to, acyclic, cyclic, or heterocyclic compounds, fused ring compounds, or phenol derivatives. The aromatic compound and the amine, boronic acid, ketone, etc. may comprise a portion of a single molecule, such that the arylation reaction proceeds as an intramolecular reaction.

In some embodiments, the amine, boronic acid, ketone, etc., are produced instantaneously by conversion of the precursor under the reaction conditions.

In some embodiments, the aryl substrate and/or amine, boronic acid, ketone, etc., are attached to the solid support either directly or via a chain (tether).

Alternatively, the corresponding salts of the amines, boronic acids, ketones, and the like may be prepared and used in place of the amines, boronic acids, ketones, and the like. When the corresponding salts of the amines, boric acids, ketones, etc. are used in the reaction, additional base may not be required.

The active form of the transition metal catalyst is not well characterized. Thus, it is intended that the "transition metal catalyst" of the present invention, as that term is used herein, shall include any catalytic transition metal and/or catalyst precursor which, when added to the reaction vessel, is immediately converted, if necessary, to the active form, as well as the active form of the catalyst participating in the reaction.

In a preferred embodiment, the transition metal catalyst complex provided in the form of a reaction mixture is a catalytic amount. In some embodiments, the amount is in the range of 0.0001 to 20 mol%, preferably in the range of 0.05 to 5 mol%, most preferably in the range of 1 to 3 mol%, and for defined reagents, it may be an aromatic amine, boronic acid, ketone, etc. (or their corresponding salts), depending on the reagent being in stoichiometric excess. In the case where the molecular form of the catalyst complex comprises more than one metal, the amount of catalyst complex used in the reaction can be adjusted accordingly. By way of example, Pd₂(dba)₃Having two metal centers, Pd used in the reaction₂(dba)₃The molar amount of (a) can be halved without loss of catalytic activity.

Catalysts containing palladium and nickel are preferred. It is desirable to use these catalysts similarly, since it is known that they can perform similar reactions, namely, oxidative addition reactions and reductive elimination reactions, which are believed to be involved in the formation of the products of the present invention. The new ligands are believed to improve the performance of the catalyst by, for example, improving reactivity and preventing unwanted side reactions.

Accordingly, the catalyst used in the process involves the use of a metal which can mediate a cross-coupling reaction of the aryl group ArX and an amine, boronic acid, ketone, etc. as defined above. In general, any transition metal (e.g., having d-electrons) can be used to form the catalyst, such as a metal selected from one of groups 3-12 of the periodic table or from the lanthanide series. However, in a preferred embodiment, the metal is selected from the latter transition metals, such as preferably a metal of groups 5 to 12 and more preferably a metal of groups 7 to 11. For example, suitable metals include platinum, palladium, iron, nickel, ruthenium, and rhodium. The particular form of metal used in the reaction is selected so as to provide a metal center under the reaction conditions which is coordinatively unsaturated and is not in its highest oxidation state. The metal center of the catalyst should be a zero-valent transition metal, such as Pd or Ni, which has the ability to undergo an oxidative addition to an Ar-X bond. The zero-valent state, M (0), may be generated, for example, in real time from M (II).

By way of further illustration, suitable transition metal catalysts include soluble or insoluble complexes of platinum, palladium, and nickel. Nickel and palladium are particularly preferred and palladium is most preferred. It is assumed that the zero valent metal center participates in the catalytic carbon-heteroatom or carbon-carbon bond forming step. Therefore, it is desirable that the metal center be in a zero-valent state or capable of being reduced to metal (0). Suitable soluble palladium complexes include, but are not limited to, tris (dibenzylideneacetone) dipalladium [ Pd₂(dba)₃]Bis (dibenzylideneacetone) palladium [ Pd (dba)]₃]And palladium acetate. Alternatively, particularly for nickel catalysts, the active species for the oxidation-addition step may be in the metal (+1) oxidation state.

It is desirable that these catalysts can be carried out similarly, since it is known in the art that they can carry out similar reactions, i.e., cross-coupling reactions, which can participate in the formation of the products of the present invention, such as aryl amines, diaryl, α -aryl ketones, and the like.

The coupling may be catalyzed by a palladium catalyst, which may be provided in the following form (for illustrative purposes only): Pd/C, PdCl₂、Pd(OAc)₂、(CH₃CN)₂PdCl₂、Pd[P(C₆H₅)₃]₄And Pd (0) supported by a polymer. In other embodiments, the reaction may be catalyzed by a nickel catalyst, which may beprovided in the following form (for illustrative purposes only): ni (acac)₂、NiCl₂[P(C₆H₅)]₂Ni (1, 5-cyclooctadiene)₂Ni (1, 10-phenanthroline)₂、Ni(dppf)₂、NiCl₂(dppf)、NiCl₂(1, 10-phenanthroline), Raney nickel, etc., wherein "acac" represents acetylacetonato.

The catalyst is preferably provided as a reaction mixture containing a metal-ligand complex bound to a support ligand, i.e., a metal-support ligand complex, the action of the ligand may be critical to promote, inter alia, reductive elimination pathways leading to products, etc., rather than side reactions such as the β -hydride elimination pathway.

As described in more detail below, the ligand may be a chelating ligand, such as, by way of example only, alkyl and aryl derivatives of phosphines and diphosphines, amines, diamines, imines, arsines and hybrids thereof, including hybrids of phosphines and amines. Weak or non-nucleophilically stable ions preferably avoid unwanted side reactions involving counterions. The catalyst complex may include additional ligands when it is desired to obtain a stable complex. Alternatively, the ligand may be added to the reaction mixture in the form of a metal complex, or as an additional reagent with respect to the metal added.

The support ligand may be added to the reaction solution as an isolated compound, or may be complexed to the metal center prior to addition of the support ligand to the reaction solution to form a metal-support ligand complex. A truncate ligand is a compound added to the reaction solution that is capable of attaching to the catalytic metal center. In some preferred embodiments, the carrier ligand is a chelating ligand. While not being bound by any theory of operation, it is hypothesized that the carrier ligand may stop unwanted side reactions and increase the speed and efficiency of the desired process. In addition, they prevent, in particular, the precipitation of catalytic transition metals. Although the present invention does not require the formation of metal-support ligand complexes, these complexes have been shown to be consistent with the hypothesis that they are intermediates in these reactions and that the choice of the support ligand has been observed to have an impact on the reaction process.

The carrier ligand is present in an amount in the range of 0.0001 to 40 mol% relative to the defined reagent, i.e. amine, boronic acid, ketone, etc., or aromatic compound. The ratio of support ligand to catalyst complex is generally in the range of about 1 to 20, preferably in the range of about 1 to 4, most preferably 2. These ratios are based on a single metal complex and a single binding site ligand. For example when the ligand contains additional binding sites (i.e. chelating ligands) or the catalyst contains more than one metalThe ratio should be adjusted. By way of example only, the support ligand, BINAP, contains two coordinating phosphorus atoms, so the BINAP to catalyst ratio is adjusted downward to about 1 to 10, preferably about 1 to 2 and most preferably 1. In contrast, Pd₂(dba)₃Containing two palladium metal centers, thereby non-chelating ligands with Pd₂(dba)₃Is adjusted upwards to 1-40, preferably 1-8 and most preferably 4.

In some embodiments of the process, the transition metal catalyst includes one or more phosphine or aminophosphine ligands, for example, as lewis base ligands, which control the stability and electron transfer characteristics of the transition metal catalyst, and/or stabilize the metal intermediate. Phosphine ligands are commercially available or can be prepared by methods analogous to known procedures. The phosphines may be monodentate phosphine ligands, such as trimethylphosphine, triethylphosphine,tripropylphosphine, triisopropylphosphine, tributylphosphine, tricyclohexylphosphine, trimethylphosphite, triethylphosphite, tripropylphosphite, triisopropylphosphite, tributylphosphite and tricyclohexylphosphite, in particular triphenylphosphine, tri (o-tolyl) phosphine, triisopropylphosphine or tricyclohexylphosphine; or bidentate phosphine ligands such as 2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), 1, 2-bis (dimethylphosphino) ethane, 1, 2-bis (diethylphosphino) ethane, 1, 2-bis (dipropylphosphino) ethane, 1, 2-bis (diisopropylphosphino) ethane, 1, 2-bis (dibutyl-phosphino) ethane, 1, 2-bis (dicyclohexylphosphino) ethane, 1, 3-bis (dicyclohexylphosphino) propane, 1, 3-bis (diisopropylphosphino) propane, 1, 4-bis (diisopropylphosphino) butane and 2, 4-bis (dicyclohexylphosphino) pentane. The aminophosphines can be monodentate ligands, e.g., the aminophosphine can only donate a catalytic metal atom, a Lewis base nitrogen atom, or a Lewis base phosphorus atom per molecule. Alternatively, the aminophosphine may be a chelating ligand, such as a Lewis base nitrogen atom and a Lewis base phosphorus atom, capable of donating catalysis to the metal atom.

In some cases, it is necessary to include additional reagents in the reaction mixture to increase the reactivity of the transition metal catalyst or the activated aryl core. In particular, it may be beneficial to include a suitable base. In general, a variety of bases can be used in the practice of the present invention. The principle of action of the base involved in the conversion at this time has not yet been clarified. The base may optionally be sterically hindered to prevent metal complexation of the base in these cases, where such complexation is possible i.e. alkali metal alkoxide. Typical bases include, by way of example only, alkoxides such as sodium t-butoxide; alkali metal amides such as sodium amide, lithium diisopropylamide and alkali metal bis (trialkylsilyl) amides such asLithium bis (trimethylsilyl) amide (LiHMDS) or sodium bis (trimethylsilyl) amide (NaHMDS); tertiary amines (e.g. triethylamine, trimethylamine, 4- (dimethylamino) pyridine (DMAP), 1, 5-diazabicyclo [4.3.0]]Non-5-ene (DBN), 1, 5-diazabicyclo [5.4.0]Undec-5-ene (DBU)); alkali or alkaline earth metal carbonates, bicarbonates or hydroxides (e.g. sodium, magnesium, calcium, barium, potassium carbonates, phosphates, hydroxides and bicarbonates). By way of example only, suitable bases include NaH, LiH, KH, K₂CO₃、Na₂CO₃、Ti₂CO₃、Cs₂CO₃、K(OtBu), Li (OtBu), Na (OtBu), K (OAr), Na (OAr) and triethylamine, or a mixture thereof. Preferred bases include CsF, K₃PO₄、DBU、NaOt-Bu、KOt-Bu、LiN(i-Pr)₂(LDA)、KN(SiMe₃)₂、NaN(SiMe₃)₂And LiN (SiMe)₃)₂。

The base is used in the process in approximately stoichiometric proportions. The present inventors have demonstrated that no excess base is required to obtain high yields of the desired product under mild reaction conditions. Not more than 4 equivalents of base are required and preferably not more than 2 equivalents. In addition, in reactions using the corresponding salts of amines, boric acid, ketones, and the like, additional bases may not be required.

As is clearly understood from the above discussion, the products that can be produced by the amination, Suzuki coupling and α -arylation reactions of the present invention can be reacted further to give the desired derivatives of the above products.

Reaction conditions

Although it is understood that the solvent and temperature ranges recited herein are not limiting and merely correspond to preferred modes of the process of the invention, the reaction of the invention can be carried out over a wide range of conditions.

Generally, it is desirable that the reaction be carried out using mild conditions that do not adversely affect the reactants, catalyst or product. For example, reaction temperature affects the reaction rate and the stability of the reactants and catalyst. The reaction is generally carried out at a temperature in the range of 25 ℃ to 300 ℃, more preferably in the range of 25 ℃ to 150 ℃.

Typically, the reaction is carried out in a liquid reaction medium. The reaction can be carried out without additional solvent. Alternatively, the reaction may be carried out in an inert solvent, preferably one in which the reaction components (including the catalyst) may be substantially dissolved. Suitable solvents include ethers such as diethyl ether, 1, 2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, etc.; aliphatic or aromatic hydrocarbon solvents such as benzene, xylene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or a mixture of two or more solvents.

The invention also contemplates conducting the reaction in a biphasic mixture of solvents, in an emulsion or suspension, or in a lipid or biphasic solvent. In some embodiments, it is preferred to carry out the catalytic reaction in a solid phase having one reactant adhered to a solid support.

In some embodiments, it is preferred that the reaction be carried out under an inert atmosphere, such as nitrogen or argon.

The reaction process of the present invention may be carried out in a continuous, semi-continuous or batch mode of manufacture and may employ liquid recycle operations if desired. Theprocess of the invention is preferably carried out in a batch production mode. Likewise, the method or sequence of addition of the reaction components, catalyst and solvent is also generally not critical to the success of the reaction and may be carried out in any conventional manner. In terms of the order of addition, generally, in some cases, the reaction rate may be increased, with a base such as t-BuONa being the last ingredient added to the reaction mixture.

The reaction may be carried out in a single reaction zone or in a plurality of reaction zones, in series or in parallel, or it may be carried out batchwise or continuously in an elongated tubular zone or in such zones in series. The materials of construction used should be inert to the starting materials in the reaction and the equipment should be able to withstand the reaction temperatures and pressures. During the course of the reaction, it may be convenient to utilize means for introducing and/or adjusting the amounts of starting materials or ingredients fed batchwise or continuously into the reaction zone in the process in order to maintain the desired molar ratios of the starting materials. The reacting step may be carried out by incrementally adding one reactant to the other reactant. The reaction steps may also be combined by adding the starting materials together to the metal catalyst. When complete conversion is not desired or is not achieved, the starting material may be separated from the product and then recycled to the reaction zone.

The process may be carried out in a glass-substrate, stainless steel or similar type of reaction equipment. The reaction zone may be equipped with one or more internal and/or external heat exchangers in order to control undue temperature fluctuations or to prevent any possible "runaway" reaction temperatures.

In addition, one or more reactants can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, derivatization with one or more substituents of the aryl group.

Combinatorial compound libraries

The reaction is readily involved in the construction of combinatorial compound libraries for compounds used to screen for pharmaceutical, agricultural or other biologically or medically relevant activities or for material quality. Combinatorial compound libraries for the purposes of the present invention are mixtures of chemically related compounds that can be screened together for a desired property; the library of compounds may be in the liquid phase or covalently attached to a solid support. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening steps that need to be performed. Screening for suitable biological, pharmaceutical, agricultural or physical properties may be carried out by conventional methods.

A diversity of compound libraries can be generated at a variety of different levels. For example, the substrate aryl groups used in the combinatorial schemes can be diverse depending on the core aryl moiety, e.g., diverse in terms of the structure of the ring, and/or can vary with other substituents.

There are many techniques available in the art for constructing combinatorial libraries of small organic molecules. See, e.g., Blondell et al (1995) Trends anal. chem.14: 83; affymax u.s. patents 5,359,115 and 5,362,899; ellman u.s. patent 5,288,514; still et al PCT publication WO 94/08051; chen et al (1994) JACS 116: 2661: kerr et al (1993) JACS 115: 252; PCT publication Nos. WO 92/10092, WO 93/09668 and WO 91/07087; and Lerner et al PCT publication WO 93/20242. Thus, libraries of different compounds at a scale of about 16 to 1,000,000 or more diversomers can be synthesized and screened for a particular activity or property.

In an exemplary embodiment, libraries of substituted diversomers can be synthesized using the reactions described adapted from the techniques described in Still et al PCT publication WO94/08051, for example, by attachment of hydrolyzable or photolyzable groups, such as groups located at one of the various positions of the substrate, to polymer resin beads (polymerbeads). According to Still et al, the library of compounds is synthesized on a set of resin beads, each of which includes a series of markers in order to identify the specific diversomer on the bead. In one embodiment, which is particularly suitable for use in discovering enzyme inhibitors, the resin beads may be dispersed on the surface of a permeable membrane, from which divers are released by cleavage of resin bead linker molecules (linker). The diversomer from each resin bead will diffuse through the membrane to the test area where it will interact with the enzyme assay. A detailed discussion of some of the combinatorial methodologies is provided below.

A) Direct characterization

A trend in the field of combinatorial chemistry is to develop the sensitivity of techniques such as Mass Spectrometry (MS), which can be used, for example, to characterize sub-femtomolar quantities of compounds and to directly determine the chemical structure of compounds selected from combinatorial libraries. For example, when providing a library of compounds that do not dissolve on a carrier matrix, a discrete population of compounds can first be released from the carrier and characterized by MS. In other embodiments, as part of the MS sample preparation technique, the MS technique, such as MALDI, may be used to release the compound from the matrix, particularly where a labile bond is initially used to attach the compound to the matrix. For example, resin beads selected from a library of compounds may be irradiated in a MALDI step to release the diversomer from the matrix andionize the diversomer for MS analysis.

B) Multiple needle combination

The compound library of the method may be in a multi-pin compound library format. Briefly, Geysen and coworkers (Geysen et al (1984) PNAS 81: 3998-. Thousands of compounds can be synthesized and screened weekly using the Geysen technique using a multi-needle method, and the series (tested) can be reused in many tests. Appropriate linker moieties may also be attached to the needle so that the synthesized compound can be cleaved from the support for purity identification and further determination (see, Bray et al (1990) Tetrahedron Lett 31: 5811-.

C) Split-coupling-recombination

In yet another embodiment, a diverse library of compounds can be provided using split-coupling-recombination strategies on a series of resin beads (see, e.g., Houghten (1985) PNAS 82: 5131-. Briefly, the term means that in each synthetic step, when introducing degeneracy into the library of compounds, the resin beads can be divided into separate groups, the number of groups corresponding to the number of different substituents added at a specific position of the library of compounds, which are coupled in separate reactions, the resin beads being recombined into one pool for the next iteration (iteration).

In one embodiment, a split-coupling-recombination strategy can be performed using a method similar to that first developed by Houghen, known as "tea bag", in which the synthesis of the compound occurs on a resin-sealed polypropylene bag with internal pores (Houghten et al (1986) PNAS 82: 5131-. Substituents can be coupled to the compound-bearing resin by placing the bag in a suitable reaction solution, in which case all conventional steps such as resin washing and deprotection can be carried out simultaneously in one reaction vessel. At the end of the synthesis, each bag contains a single compound.

D) Combined compound library for photoalignment space positioning parallel chemical synthesis

By virtue of their localization in synthetic substrates, combinatorial synthesis systems in which compounds are defined are called spatially-addressable syntheses. In one embodiment, the combination procedure is performed by controlled addition of chemical reagents to specific locations on a solid support (Dower et al (1991) Annu Rep Med Chem 26: 271-280; Fodor, S.P.A. (1991) Science 251: 767; Pirrung et al (1992) U.S. Pat. No. 5,143,854; Jacobs et al (1994) Trends Biotechnol 12: 19-26). The spatial decomposition of lithography provides miniaturization. This technique can be accomplished by using a protection/deprotection reaction with a non-light-resistant protecting group.

The technical gist is described by Gallop et al (1994) J Med Chem 37: 1233 and 1251. Synthetic substrates for coupling are prepared by a light-labile nitroveratryl oxycarbonyl (NVOC) covalent attachment protected amino linker molecule or other light-labile linker molecule. Photo-selective activation is used for coupling defined regions of the synthetic support. Deprotection of the photolabile protecting group by light (deprotection) results in activation at selected regions. After activation, the first plurality of amino acid analogs, each bearing a non-light-resistant protecting group at the amino terminus, are exposed on the entire surface. Coupling occurs only in the areas located by the light guide in the previous step. The reaction was stopped, the plate washed and the substrate was illuminated again with a second mask (mask) to activate a different area for reaction with a second protective building block. The pattern of the mask and the sequence of the reactants determine the type and location of the product. Since the process utilizes photolithographic techniques, the number of compounds that can be synthesized is limited to the number of synthesis sites that can be located with appropriate resolution. Thus, knowing the position of each compound unambiguously allows the targeted determination of its interaction with other molecules.

In photo-directed chemical synthesis, the product depends on the mode of irradiation and the order of addition of the reactants. By varying the lithographic pattern, many different groups of test compounds can be synthesized simultaneously; the characteristics lead to many different mask strategies.

E) Coding combinatorial compound libraries

In another embodiment, the method utilizes a library of compounds having a coded label system. Recent improvements in the identification of active compounds from combinatorial compound libraries have applied chemical indexing systems using tags that uniquely encode the reaction steps that the resulting beads have undergone, such as the structure that it has. Theoretically, this pathway mimics phage to represent a library of compounds in which the activity is derived from the expressed peptide, but the structure of the active peptide is deduced from the corresponding chromosomal DNA sequence. The first code for the synthesis of the combinatorial compound library uses DNA as a code. Many other forms of coding have been reported, including coding with orderable bio-oligomers (e.g., oligonucleotides and peptides), as well as binary coding with additional non-orderable tags.

1) Label with sequencable biological oligomer

The principle of using oligonucleotide-coded combinatorial synthesis of libraries was described in 1992 (Brenner et al (1992) PNAS 89: 5381-5383), and examples of such libraries were published in the next year (seeds et al (1993) PNAS 90: 10700-10704). Is referred to as 7⁷The combinatorial compoundlibrary of peptides (═ 823,543) includes all Arg, Gln, Phe, Lys, Val, D-Val and Thr (three letter amino acid code) combinations, each of which is encoded by a specific dinucleotide (TA, TC, CT, AT, TT, CA and AC respectively), prepared from a series of alternating circular forms of the peptide and oligonucleotide synthesis on a solid support. In said products, the linking functionality of the amine on the resin beads is particularly different from peptide or oligonucleotide synthesis, which results in the generation of OH groups for oligonucleotide synthesis and the protection of NH groups for peptide synthesis by simultaneous pre-incubation of the resin beads with reagents₂Groups (here in a ratio of 1: 20). When complete, the tags each contain 69-mer (mers), 14 with encoded units. The resin bead-bound compound library is derived from fluorescently labeled antibodies, and resin beads containing conjugated antibodies with strong fluorescence are harvested by Fluorescence Activated Cell Selection (FACS) instrument. The expected peptides were synthesized by PCR amplification of the DNA markers and sequencing. After these techniques, derivatizationLibraries of compounds are used in the method, wherein the sequence of the labelled oligonucleotides determines the sequence combination reaction carried out by a particular resin bead, thus resulting in the determination of the compounds on the resin bead.

The use of oligonucleotide labels makes it possible to perform sensitive analysis of photosensitive labels. Nevertheless, this approach requires careful selection of orthogonal sets of protecting groups (orthogonal sets) that are required for alternate re-synthesis of the tag and the library members of the compound. On the other hand, libraries of labeled chemical compounds, particularly phosphate and carbohydrate anomeric linkage (anomericlinnkage), may limit the choice of reagents and conditions that may be used for the synthesis of non-oligomeric compound libraries. In apreferred embodiment, the compound library uses a linker that allows selective separation of the test compound library members for the assay.

Polypeptides have also been used as tag molecules for combinatorial compound libraries. Two typical methods are disclosed in the art, both using branched linkers and additionally elaborated ligand chains attached to the encoded solid phase. In the first method (Kerr JM et al (1993) J Am ChemSoc 115: 2529-2531), orthogonality in the synthesis was achieved by using acid-sensitive protection of the coding strand and base-sensitive protection of the compound strand.

In an alternative approach (Nikolaiev et al (1993) Pept Res 6: 161-170), a branched linker molecule is used to attach both the coding unit and the test compound to the same functional group on the resin. In one embodiment, a cleavable linker molecule is disposed between the branch point and the resin bead to allow the isolate to release the molecule containing the coding and compound (Ptek et al (1991) Tetrahedron Lett 32: 3891-3894). In another embodiment, a detachable linker molecule may also be coupled so that the test compound may be selectively detached from the resin beads, leaving behind the code. This novel structure is particularly valuable because it allows screening test compounds without interference from potential coding groups. The examples in the art of independent isolation and sequencing of members of a library of polypeptide compounds and their corresponding tags have demonstrated that the tags can accurately predict the structure of the polypeptide.

2) Non-sequenceable tags: binary coding

Another form of library of coding test compounds uses a set of non-sequenceable electronic tag molecules that can be used as binary codes (Ohlmeyer et al (1993) PNAS 90: 10922-10926). Typical labels are halogenated aromatic alkyl ethers, which are in the form of trimethylsilyl ethers that can be detected by Electron Capture Gas Chromatography (ECGC) at less than femtomolar levels. The change in the length of the alkyl chain, as well as the change in the nature and position of the aromatic halide substituent, allows synthesis on at least 40 such tags, which in principle can encode 2⁴⁰(e.g., 10)¹²Above) different molecules. In the initial report (Ohlmeyer et al, supra), tags were attached to approximately 1% of the available amine groups of a library of polypeptide compounds by a photocleavable ortho-nitrobenzyl linker molecule. The method is convenient when preparing combinatorial libraries of peptoids or other amine-containing molecules. However, more feasible systems have been developed that allow programming of essentially any combinatorial compound library. Wherein the compound can be attached to a solid support by a photocleavable linker and the tag can be attached by insertion of a catechol ether linker into the matrix of resin beads via carbene (Nestler et al (1994) J OrgChem 59: 4723-4724). The orthogonal attachment strategy allows selective desorption of the compound library members for solution state determination and subsequent decoding by ECGC after oxidative desorption of the tag population.

While some amide-linked compound libraries in the art use binary codes with electronic tags attached to amine groups, directly attaching these tags to the resin bead matrix provides more versatility in the structures that combinatorial compound libraries can be prepared. In this way the tags and their linker molecules may be as little reactive as their resin bead matrix. Two binary programming combinatorial compound libraries have been reported in which an electronic tag is attached directly to a solid phase (Ohlmeyer et al (1995) PNAS 92: 6027-6031) and provides a guide for the construction of the compound library. An orthogonal attachment strategy is used to construct two libraries of compounds in which the library members are attached to a solid support by a photosensitive linker molecule and the tags are only attached by a detachable linker molecule with strong oxidation. Because the library of compounds can be photon eluted from the solid support multiple times in part (photoeluted), the library of compounds can be used in a variety of assays. Continuous photon elution also allows very high throughput of repeated screening strategies: first, a plurality of resin beads were placed in a 96-well microtiter plate; second, the compound fractions are separated and transferred to a test plate; third, the metal binding assay determines active pores; fourth, the corresponding resin beads are singly rearranged into a new microtiter plate; fifth, a single active compound is identified; and sixth, decoding the structure.

Examples

The present invention may be understood by reference to the following examples, which are intended to be illustrative only and not limiting. The substrates used in the examples can be purchased or prepared from commercially available reagents.

Example 1

High activity catalysts for palladium catalyzed cross-coupling reactions: suzuki coupling and amination of inactive aryl chlorides at room temperature

Highly active palladium catalysts have been developed which use the chelating aminophosphine ligand 1- (N, N-dimethylamino) -1' - (dicyclohexylphosphino) biphenyl (2). The catalyst is effective for cross-coupling of aryl chlorides with amines, boronic acids and ketone enolates. The sufficient reactivity of the system is suitable for room temperature amination of aryl bromides and electron-deficient aryl chlorides, and facilitates room temperature Suzuki coupling reactions of multi-electron and electron-deficient aryl chlorides. Coordination of the amine moiety is critical to enhance reactivity and catalyst stability of the system.

Palladium-catalyzed C-N bond-forming reactions have involved versatile and efficient synthetic transformations. Use of a palladium catalyst supported by bidentate phosphine ligands to effect nitrogen transfer¹Oxygen, oxygen²And some carbon nucleophiles³Substituted aryl halides and triflates are possible. For aryl chloride substitution reactions^4，5The lack of generic palladium-based catalysts, and the frequent need to raise the reaction temperature, prompted us to investigate new ligands that could overcome these limitations.

In our laboratory, by BINAP/Pd (OAc)₂Catalytic amination of aryl bromides¹H NMR studies suggest that an increase in oxidation may limit the rate.⁶For aryl chlorides, it is expected that increased oxidation will make them more inert. To slow down the magnitude of this slow down, we began to investigate the use of polyelectron phosphine ligands.^4，5d，7aUsing a PC_Y3Initial experiments as palladium support ligands demonstrated that although such catalysts were able to activate carbon-chlorine bonds, this process was compromised by the facile elimination of β -hydride and subsequent formation of reduced aromatics.^5aTo our knowledge, bidentate ligands inhibit β -hydride elimination in the arylation of primary amines,^1cwe will focus on the preparation of multi-electron bidentate phosphines.⁶We first prepared the known 1, 1' -bis (dicyclohexylphosphino) binaphthyl (1).⁸Preliminary screening confirmed that 1/Pd (0) formed a catalyst that was quite effective for coupling pyrrolidine to chlorotoluene. This important result, combined with our bidentate monophosphines PPF-OMe and PPFA^1dThe experience of (2) has prompted us to prepare aminophosphine ligands 2.⁹The use of ligand 2 compared to 1 is generally superior and broadly extends the range of palladium-catalyzed aryl chloride conversions. In this context, we have demonstrated that the 2/Pd (0) catalyst system has high activity and can be used in the first example of room temperature amination of aryl bromides and room temperature amination of aryl chlorides. And, the system functions as the first common catalyst for room temperature Suzuki coupling reactions of aryl chlorides.

To demonstrate the effectiveness of the 2/Pd (0) catalyst system, we have prepared different aniline derivatives from aryl chlorides (Table 1, items 1-2, 4-6, 8-9, 13, 16). The secondary amines had excellent effect in the coupling step (Table 1, items 1-2, 4-6, 8-9), and the arylation of the primary anilines could also be accomplished (Table 1, item 16). Primary alkylamines are effective coupling partners, provided that the aryl chlorides are substituted in the ortho position (Table 1, item 13), or by means of the use of ligand 1 (Table 1, items 14, 17). Catalyst levels as low as 0.05 mol% Pd in the reaction of chlorotoluene with di-n-butylamine were achieved (Table 1, item 1).

Given the high reactivity of the catalyst, we analyzed the possibility of performing room temperature amination. We have found that aryl iodides and aryl bromides (table 1,

items

3, 7, 10, 15) readily react at room temperature when DME is used as the solvent. The experimental single step did not require crown ether or other additives.^1eIn summary, room temperature amination of aryl bromides shows the same working domain as reaction of aryl chlorides at 80 ℃. By using K₃PO₄As a base, aryl bromides containing NaOt-Bu sensitive functional groups can be converted to the corresponding aniline derivatives. In these reactions (Table 1, items 11and 12), in order to reduce K₃PO₄The alkalinity and/or solubility of (a) requires heating at 80 ℃.

The first amination using aryl chlorides of 2/Pd (0), even activated aryl chlorides, can be accomplished at room temperature for the first time.¹⁰Thus, from 2.5 mol% Pd₂(dba)₃DME solutions of 7.5 mol% 2 and NaOt-Bu catalyzed coupling of p-chlorobenzonitrile and morpholine at room temperature gave the corresponding aniline derivative in 96% yield (Table 1, entry 9).

Table 1: catalytic amination of aryl chlorides and bromides^a

(a) Reaction conditions are as follows: 1.0 equivalent of aryl halide, 1.2 equivalents of amine, 1.4 equivalents of NaOtBu, 0.5 mol% Pd₂(dba)₃1.5 mol% ligand (1.5L/Pd), toluene (2mL/mmol halide), 80 ℃. In 1The reaction is completed within 1 to 27 hours; the number of reactions was not minimized. (b) The reaction was carried out in DME solvent at room temperature. (c) Reaction with 1.5 mol% Pd₂(dba)₃All together. (d) Reaction with 2.5 mol% Pd₂(dba)₃All together. (e) Using K₃PO₄And reacting with DME solvent. (f) Using Pd (OAc)₂、K₃PO₄And reacting with DME solvent. (g) Only one of the two runs was carried out to achieve 98% conversion. (h) The reaction was carried out at 100 ℃. (i) And Pd (OAc)₂ Ligand 1, Cs₂CO₃As a catalyst, a ligand and a base together. (j) 1 was used as ligand. (k) [ ArBr]]＝1M。(l)[ArBr]2M. (m) 1.5 equivalents of benzylamine are used.

Based on the high reactivity of this new catalyst system in the amination reaction, we examined its efficacy in a variety of different Pd-catalyzed C — C bond formation reactions. Pd-catalyzed Suzuki coupling reaction¹¹The use of chloride as a substrate for the reaction generally requires relatively high reaction temperatures (>90 ℃) and is often ineffective if the aryl halide does not contain an electron-withdrawing substituent.⁷Although nickel catalysts are more effective in promoting electron-neutral or multi-electron aryl chloride Suzuki coupling reactions, sterically hindered substrates often present problems due to the small volume of nickel relative to palladium.¹²In addition, an example of a Suzuki coupling reaction carried out at room temperature isRare, and often require stoichiometric amounts of highly toxic thallium hydroxide.^13b、c、dTo our knowledge, no example of room temperature Suzuki coupling of aryl chlorides has been reported.

We have found that the use of a 2/Pd (0) catalyst system and CsF¹⁴The Suzuki coupling reaction of aryl bromide and aryl chloride was carried out in high yield in dioxane solvent at room temperature (table 2,

entries

2, 5, 7-10).^15、16These conditions apply to the coupling of multiple electrons and the absence of an electron aryl chloride and allow for the presence of base sensitive functional groups. Use instant 1-hexane and 9-BBN¹⁷The aryl-alkyl coupling reaction of the resulting alkylboron reagent, aryl chloride, may be at 50 deg.CCompleting the process; it is speculated that higher temperatures are required in order to increase the volume of the boron reagent and slow the rate of alkyl transmetallation associated with the aryl group.¹⁷Suzuki coupling of multi-electron aryl chlorides also makes it possible to use inexpensive K₃PO₄With only 0.5 mol% of palladium catalyst, although temperatures of 100 ℃ are required.

We have also found that the 2/Pd (0) catalyst system is effective for Pd-catalyzed α-arylation of ketones.³The coupling of 5-bromo-m-xylene with 2-methyl-3-pentanone can be performed at room temperature using NaHMDS as the base (table 2, item 12). Significantly, the BINAP catalyst system was chosen in promoting the monoarylation of the methylketones, while 2/Pd was chosen for the biarylation of the methylketones (Table 2, entry 11). This may be due to the reduction in steric bulk of the dimethylamine moiety of 2, which is associated with the diphenylphosphine group of BINAP.

Pd-catalyzed cross-coupling of other aryl chlorides was identified using the catalyst. Still coupling,¹⁸Sonogashira coupling¹⁹And cross-coupling of aryl halides with organozinc reagents did not yield detectable products.²⁰Heck arylation of styrene²¹Some product was converted at 110 ℃.

Table 2: suzuki coupling^aAnd Ketone arylation

(a) Reaction conditions are as follows: 1.0 equivalent of aryl halide, 1.5 equivalents of boron reagent, 3.0 equivalents of CsF, 0.5-2.0 mol% Pd (OAc)₂0.75-3.0 mol% 2(1.5L/Pd), dioxane (3mL/mmol halide), the reaction was complete in 19-30 hours; the number of reactions was not minimized. (b) 2.0 equivalents of K are used₃PO₄Instead of CsF. (c) Only one of the two steps was carried out to achieve 98% conversion. (d) Using Pd₂(dba)₃NaOtBu as catalyst and base. (e) Using Pd₂(dba)₃NaHMDS as catalyst, base.

Although the exact mechanism of reaction promotion by the 2/Pd (0) catalytic system is still notIt is known, but we believe that the overall catalytic ring for the amination reaction is similar to the rationale postulated for BINAP/Pd catalyzed amination of aryl bromides.^1cHowever, when catalyzed by 2/PdThere may be different routes in the reaction for the amine complexation/deprotection step. We now disclose a route involving the attachment of an amine to a tetra-ligand complex I, followed by deprotection of the resulting penta-ligand complex II to give III (Table 1, route A). On the other hand, following initial dissociation of the dimethylamino portion of the ligand, complexation of the amine substrate may occur, followed by complexation of the amine substrate at the tri-ligand^22bNucleophilic chemical reaction on the complex IV to obtain V. Subsequent deprotection of V to III (fig. 1, route B) by rapid re-complexation of the ligand amine groups.²²If pathway B is followed, re-complexation of the amine may be faster than elimination of β -hydride, since little or no reduction by-product generation is observed₂PPh is not an effective ligand for any of these Pd-catalytic steps;^15，16with polyelectron monodentate phosphines as ligands, e.g. Cy₃P or Cy₂The amination reaction carried out by PPh demonstrates that the absence of chelating groups on the ligand by the reduction reaction eliminated by β -hydride can be a significant problem the relatively small volume of amine groups in 2 allows both cyclic and acyclic secondary amines to be efficiently coupled.^1dThe 2/Pd (0) can be used in the amination step at a level of 0.05 mol% (table 1, item 1), suggesting that the dimethylamino group may also contribute to the stabilization of the catalyst.

FIG. 1 shows a schematic view of a

The failure of the 2/Pd (0) catalyst system to promote the Heck, Stille, Sonogashira, and Zinc cross-coupling reactions suggests that the C-C bond formation reaction discussed herein attaches to metals through both the tetra-ligand intermediate and the amine and phosphine moieties in a key step of the catalytic cycleTo proceed with. If the ligands are linked in bidentate form, the transmetallation from Sn, Cu or Zn, or coordination of the olefin, will beSlowly.^21，23The following facts support the theory that Suzuki coupling and Ketone arylation reactions are generally efficient using chelating phosphine ligands, but not efficient for Stille reactions. Although Heck reactions are effective in some cases with chelating ligands, they typically use cationic complexes or for intramolecular reactions.²¹

We expect that this modification of ligand design or further optimization of reaction conditions can lead to efficient Heck olefination of polyelectron aryl chlorides.²⁴Intensive research is currently being conducted into the development of high-activity catalysts for these processes or other processes.

Reference and comments to example 1

(1)(a)Guram，A.S.；Rennels，R.A.；Buchwald，S.L.Angew.Chem.Int.Ed.Engl.1995，34，1348-1349；(b)Wolfe，J.P.；Rennels，R.A.；Buchwald，S.L.Tetrahedron 1996，52，7525-7546.(c)Wolfe，J.P.；Wagaw，S.；Buchwald，S.L.J.Am.Chem.Soc.1996，118，7215-7216；(d)Marcoux，J.-F.；Wagaw，S.；Buchwald，S.L.J.Org.Chem.1997，62，1568-1569；(e)Wolfe，J.P.；Buchwald，S.L.J.Org.Chem.1997，62，6066-6068.(f)Wolfe，J.P.；Wagaw，S.；Marcoux，J.-F.；Buchwald，S.L.Acc.Chem.Res.Submitted forpublication；(g)Louie，J.；Hartwig，J.Tetrahedron Lett.1995，36，3609-3612；(h)Driver，M.S.；Hartwig，J.F.J.Am.Chem.Soc.1996，118，7217-7218；(i)

，D.；Mann，G.；Hartwig，J.F.Gur.Org.Chem.1997，1，287-305.(i)Hartwig，J.F.Synlett 1997，329-340.

(2)(a)Palucki，M.；Wolfe，J.P.；Buchwald，S.L.J.Am.Chem.Soc.1996，118，10333-10334；(b)Palucki，M.；Wolfe，I.P.：Buchwald，S.L.J.Am.Chem.Soc.1997，119，3395-3396；(d)Mann，G.；Hartwig，J.F.J.Am.Chem.Soc.1996，118，13109-13110；(e)Mann，G.；Hartwig，J.F.J.Org.Chem.1997，62，5413-5418.

(3)(a)Palucki，M.；Buchwald.S.L.J.Am.Chem.Soc.1997，119，11108-11109；(b)_hman，J.；Wolfe，J.P.；Troutman，M.V.；Palucki，M.；Buchwald，S.L.J.Am.Chem.Soc.1998，120，1918；(c)Hamann，B.C.；Hartwig，J.F.J.Am.Chem.Soc.1997，119，12382-12383；(d)Satoh，T.；Kawamura，Y.；Miura，M.；Nomura，M.Angew.Chem.Int.Ed.Engl.1997，46，1740-1742.

(4) Aryl chlorides are attractive starting materials from a price and availability standpoint, but are less reactive than aryl bromides and iodides. Reference: grushin, v.v.; alper, H.chem.Rev.1994, 94, 1047-1062.

(5) The existing literature for aryl chloride amination includes our research on nickel catalysis and two palladium-based processes. Our nickel-based studies are quite effective on most of the various aryl chloride substrates, are not effective for amination of other aryl halides and do not tolerate base-sensitive functional groups. The palladium process is rather limited in scope of use and often leads to mixing of the products. See:

(a)Wolfc，J.P.；Buchwald，S.L；J.Am.Chem.Soc.1997，119，6054-6058；(b)Beller，M.；Riermeier，T.H.；Reisinger，C.-P.；Herrmann，W.A.Tetrahedon Lett.1997，38，2073-2074；(c)Riermeier，T.H.；Zapf，A.；Beller，M.Top.Catal.1997，4，301-309；(d)Reddy，N.P.；Tanaka，M.Tetrahedon Lett.1997，38，4807-4810.(e)Nishiyama，M.；Yamamoto，T.；Koie，Y.Tetrahedron Lett.1998，39，617-620；(f)Yamamoto，T.；Nishiyama，M.；Koie，Y.Tetrahedron Lett.1998，39，2367-2370.

(6) similar NMR experiments have recently been reported by Hartwigand Hamann. They have also shown that multi-electron bidentate bis-phosphines can be used for Pd-catalyzed amination of aryl chlorides: hartwig, j.f.; hamann, b.c. submitted for Publication.

(7)(a)Shen，W.Tetrahedron Lett.1997，38，5575-5578.(b)Beller，M.；Fischer，H.；Herrmann，W.A.；Ofele，K.；Brossmer，C.Angew.Chem.Int.Ed.Engl.1995，34.1848-1849.

(8)Zhang，X.；Mashima，K.；Koyano，K.；Sayo，N.；Kumobayashi，H.；Akutagawa，S.；Takaya，H.J.Chem.Soc.Perkin Trans.I 1994，2309-2322.

(9) Ligand 2 was prepared from N, N-dimethyl-2-bromoaniline in 3 steps. The ligand is obtained as a crystalline solid and stored and processed in air without any special protective measures. Under these conditions, the ligand is stable for at least one month without any appreciable oxidation. See supporting data for full experimental details.

(10) Control experiments carried out in the absence of palladium gave no coupling product after 24 hours at room temperature.

(11)Suzuki，A. in Metal-Catalyzed Cross-Coupling Reactions Diederich，F.；Stang，P.J.Eds.，Wiley-VCH，Weinheim，Germany，1998，Ch.2.

(c)Bumagin，N.A.；Bykov.V.V.Tetrahedron 1997，53，14437-14450.(d)Mitchell，M.B.；Wallbank，P.J.Tetrahedron Lett.1991，32，2273-2276.(e)Firooznia，F.；Gude，C.；Chan，K；Satoh，Y.Tetrahedron Lett.1998，39，3985-3988.(f)Cornils，B.Orgn.Proc.Res.Dev.1998，2，121-127.

(12)(a)Indolese，A.F.Tetrahedron Lett.1997，38，3513-3516.(b)Saito，S.；Oh-tani，S.；Miyaura，N.J.Org.Chem.1997，62，8024-8030.

(13)(a)Campi，E.M.；Jackson，W.R；Marcuccio，S.M.；Naeslund，C.G.M J.Chem.Soc.，Chem.Commun.1994，2395.(b)Anderson，J.C.；Namli，H.；Roberts，C.A.Tetrahedron 1997，53，15123-15134.(c)Anderson，J.C.；Namli， H.Synlett 1995，765-766.(d)Uenishi，J.-i.；Beau，J.-M.；Armstrong，R.W.；Kishi，Y.J.Am.Chem.Soc.1987，109，4756-4758.

(14)Wright，S.W.；Hageman，D.L.；McClure，L.D.J.Org.Chem.1994，59，6095-6097.

(15) For details of all experiments, see supporting information

(16) Control run using dicyclohexylphenylphosphinate instead of 2The product was obtained with low conversion and low yield.¹⁵

(17)Miyaura，N.；Ishiyama，T.；Sasaki，H.；Ishikawa，M.；Saroh，M.；Suzuki，A.J.Am.Chem.Soc.1989，111，314-321.

(18)Stille，J.K.Angew.Chem.Int.Ed.Engl.1986，25，508.

(19)Sonogashira，K.in ref 11，Ch 5.

(20)Knochel，P.in ref 11，Ch 9.

(21)(a)de Meijere，A.；Meyer，F.E.Angew.Chem.Int.Ed.`Engl.1994，33，2379-2411；(b)Br_se，S.；de Meijere，A.in ref.11，Ch.3.

(22) (a) possibly also reductive elimination of the 3-coordinated intermediate formed by deprotection of V^1j. (b) This is a condition for one phosphine dissociation chelating a bisphosphine.^1j(c) In reactions using NaOt-Bu as a base, it is possible that the complex represented in fig. 1 may contain X ═ OtBu.^2dIn the use of Cs₂CO₃Or K₃PO₄In the reaction as a base, Cs is present because of its comparison with NaOt-Bu₂CO₃And K₃PO₄Low solubility and low nucleophilicity, carbonate or phosphate complex formation is less likely.

(23)Farina，V.Pure Appl.Chem.1996，68，73-78。

(24) Heck reactions of aryl chlorides generally require high reaction temperatures and are often ineffective for multi-electron aryl chlorides. Reference 5a and references herein.

(a)Herrmann，W.A.；Brossmer，C.；Reisinger，C.-P.；Riermeier，T.H.；_fele，K.；Beller，M.Chem.Eur.J.1997，3，1357-1364.(b)Reetz，M.T.；Lohmer，G.；Schwickardi，R.Angew.Chem.Int.Ed.Engl.1998，37，481-483.(c)Ohff，M.；Ohff，A.；van der Boom，M.E.；Milstein，D.J.Am.Chem.Soc.1997，119，11687-11688.

Data relating to example 1

Summary of the invention. All reactions were carried out in a dry glass instrument under argon atmosphere. From E&Elemental analysis was performed by RMicroanalytical Laboratory, Inc., Parsippany, N.J. Toluene was distilled from molten sodium under nitrogen atmosphere. THF was distilled from sodium benzophenone ketyl under argon. The commercially available metals used were not purified, except as otherwise indicated. Aryl halides were purchased from Aldrich Chemical, except 4-chloroacetophenone was purchased from Fluka Chemical. Preparation of N, N-dimethyl-2-bromoaniline by alkylation of 2-bromoaniline with methyl iodide in DMF in the presence of sodium carbonate¹. Potassium phosphate tribasic was purchased from Fluka Chemical company. Cesium fluoride was purchased from Strem Chemical and ground with a mortar and pestle prior to use. Cesium carbonate was purchased from chemetall and ground with a mortar and pestle prior to use. Phenylboronic acid, chlorodicyclohexylphosphine, palladium acetate, tris (dibenzylideneacetone) dipalladium (0), (±) -2, 2 '-dibromo-1, 1' -binaphthyl, and n-butyllithium were purchased from Strem Chemical. Method according to conventional prescription²Lithiation from the corresponding halides and reaction with B (OMe)₃Reaction to prepare 2-methoxyphenylboronic acid²And 3-methylphenylboronic acid². These boronic acids were obtained in about 85-95%purity after crystallization from pentane/ether and were used without further purification. Trimethyl borate, triisopropyl borate, 9-BBN (0.5M in THF), NaHMDS (95%), 2-methyl-3-pentanone, 3-methyl-2-butanone, anhydrous dioxane, anhydrous DME, dicyclohexylphenylphosphine, and 1-hexene were purchased from Aldrich Chemical. Preparation of (+ -) -2, 2 '-bis (dicyclohexylphosphino) -1, 1' -binaphthyl l using a procedure analogous to that for the synthesis of (+ -) -BINAP, metallation of the corresponding dibromobinaphthyl with tert-butyllithium and quenching with chlorodicyclohexylphosphine³。⁴By elemental analysis and analysis¹H and³¹the spectrum of the P NMR is characterized by comparison with literature data.³Preparation of tetrakis (triphenylphosphine) according to literature proceduresPalladium (II).⁵Sodium t-butoxide purchased from Aldrich Chemical; most of the metals were stored in a Vacuum Atmospheres dry box (glovebox) under nitrogen atmosphere. A small portion (1-2g) was taken from the drying cabinet of the glass bottle, stored in the drying cabinet air filled with anhydrous sodium sulfate and weighed in the air. The IR spectra reported herein were obtained by placing the pure samples directly on top of the DiComp probe of the IR tester ASI REACTIR on-the-fly. The yields in tables 1 and 2 represent the isolated yields (average of two steps) of the calculated compounds, from¹HNMR, GC analysis or combustion analysis determined a purity of 95%. The number 1 of the symbols in table 1,⁶2，⁷3，⁶4，⁶5，⁸6，⁹7，⁶8，⁶9，¹¹13，⁶and (3) a (14) of,¹⁰the items have been reported previously by said groups and their¹H NMR spectra of samples prepared prior to this study¹H NMR spectral comparisons are characteristic and their purity is determined by GC analysis. The steps described in this section are representative, and thus yields may differ from those given in tables 1 and 2.

2- (N, N-dimethylamino) -2' - (dicyclohexylphosphino) biphenyl (2)

Under the cleaning of argon, N-dimethylamino-2-bromoaniline¹(4.0g, 20.0mmol) was loaded into an oven-dried flask that had been cooled to room temperature. The flask was purged with argon and THF (20mL) was added. The solution was cooled to-78 ℃ and n-butyllithium (13.1mL, 21.0mmol, 1.6M in hexanes) was added dropwise with stirring. After the addition was complete, the reaction mixture was stirred at-78 ℃ for 75 minutes, during which time a white precipitate was produced. An additional amount of 70mL of THF was added and the aryl lithium suspension was transferred by cannula to a separate flask that had been cooled to-78 deg.C containing a solution of triisopropyl borate (9.2mL, 40.0mmol) in THF (20 mL). Will be provided withThe reaction mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred overnight (25 hours). The reaction was quenched with 1M aqueous HCl (250mL) and stirred at room temperature for 15 min. The pH of the mixture was adjusted to pH7 with 6M aqueous NaOH and the mixture was transferred to a separatory funnel. The mixture was extracted with ether (3X 150mL), and the combined was dried over anhydrous magnesium sulfateThe organic extracts were concentrated in vacuo to give a brown oil containing a large amount of N, N-dimethylaniline. The oil was then taken up in ether (100mL) and extracted with 1M aqueous NaOH (3X 100 mL). The organic layer was discarded and the aqueous extract was adjusted to pH7 with 6M aqueous HCl. The aqueous layer was then extracted with ether (3X 100mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 1.85g of 2- (N, N-dimethylamino) phenylboronic acid¹²As a viscous brown oil, is obtained by¹H MR was found to be about 50-60% pure. This material was used without further purification.

The crude boric acid was taken up in ethanol (5mL) under argon and added to a solution containing tetrakis (triphenylphosphine) palladium⁵(700mg, 0.61mmol, 5 mol%) and 2-bromoiodobenzene (4.1g, 14.5mmol) in DME (100mL) in a flask. Mixing Na₂CO₃A degassed water (30mL) solution (6.42g, 60.6mmol) was added to the reaction vessel and the mixture was heated to reflux for 48 h. The reaction mixture was then cooled to room temperature, diluted with ether (200mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (200mL), the layers were separated and the aqueous layer was removed. The combined organic layers were then washed with 1M aqueous NaOH (50mL) and the aqueous washes were discarded. The combined organic fractions were then extracted with 1M aqueous HCl (4X 150 mL). The organic portion was discarded and the combined aqueous acidic extracts were basified to pH 14 with 6M aqueous NaOH. The aqueous layer was extracted with ether (3X 150mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.1g of a white solid which was purified by filtration¹H NMR confirmed the purity to be about 90-95%. This material was used without further purification.

The dried round bottom flask was cooled to room temperature under argon purge and loaded with crude 1- (N, N-dimethylamino) -1' -bromobiphenyl. The flask was purged with argon and THF (120mL) was added. The solution was cooled to 78 ℃ with stirring and n-butyllithium (5.2mL, 8.37mmol, 1.6M in hexanes) was added dropwise. The solution was stirred at-78 ℃ for 35 minutes, then chlorodicyclohexylphosphine (2.21g, 9.51mmol) in THF (30mL) was added dropwise to the reaction vessel. Will be reversedIs mixed inStir at-78 ℃ and warm slowly to room temperature overnight. The reaction was then quenched with saturated aqueous NH₄Cl (30mL) was quenched, diluted with ether (200mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid. The crude was recrystallized from degassed hot ethanol under argon to give 2.25g (29% overall yield over 3 steps) of a white solid: mp110 ℃;

¹H NMR(300MHz，CDCl₃)δ7.54(d，1H，J＝6.8Hz)，7.26-7.40(m，4H)，7.02-7.05(m，1H)，6.93-6.98(m，3H)，2.44(s，6H)，1.98-2.05(m，1H)，1.40-1.82.(m，11H)，0.75-1.38(m，10H)；¹³C NMR(125MHz，CDCl₃)δ151.5，149.8，149.5，135.8，135.5，135.3，132.7，132.4，130.54，130.49，128.5，128.1，125.8，120.6，117.3，43.2，36.8，36.7，33.5，33.4，30.9，30.8，30.6，30.4，29.8，29.7，28.5，27.6，27.54，27.46，27.3，27.2，26.7，26.4

(due to the complexity of the P-C cleavage observation; no unambiguous localization has been given);³¹P NMR(121.5MHz、CDCl₃) Delta-92; IR (pure, cm)^-1)2922, 1444, 745. For C₂₆H₃₆Analytical calculations of NPs: c, 79.35; h, 9.22. Measured value: c, 79.43; h, 9.48. General procedure for palladium catalyzed amination of aryl chlorides: the oven dried Schlenk tube or test tube fitted with a rubber septum was purged with argon and charged with tris (dibenzylideneacetone) dipalladium (0.005mmol, 1 mol% Pd), ligand 2(0.015mmol, 1.5 mol%) and NaOt-Bu (1.4 mmol). The tube was purged with argon and toluene (2.0mL), the aryl chloride (1.0mmol) and the amine (1.2mmol) were added. The mixture was stirred in an 80 ℃ oil bath until complete consumption ofthe starting aryl chloride was determined by GC analysis. The reaction mixture was then cooled to room temperature, diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude was then purified by flash chromatography on silica gel.

N- (4-methylphenyl) -p-methoxyaniline¹³

The general procedure, except using a reaction temperature of 100 ℃, gave 198mg (93%) of a brown solid:

mp 80-81℃(lit.¹³mp 84-85℃).¹H NMR(300MHz，CDCl₃)δ6.98-7.05(m，4H)，6.80-6.86(m，4H)，5.37(s，br 1H)，3.76(s，3H)，2.26(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 154.8, 142.4, 136.7, 129.7, 129.3, 121.1, 116.6, 114.7, 55.6, 20.5; IR (pure, cm)^-1)3416，2910，1513，1304，815.

N-benzyl-p-toluidine¹⁴

The general procedure and 1.5 equivalents of benzylamine, except using 1 as ligand, gave 177mg (90%) of a light yellow oil:

¹H NMR(250MHz，CDCl₃)δ7.25-7.39(m，5H)，6.98(d，2H，J＝8.1Hz)，6.56(d，2H，J＝8.5Hz)，4.31(s，2H)，3.90(br s，1H)，2.23(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 145.9, 139.7, 129.7, 128.5, 127.4, 127.1, 126.7, 113.0, 48.6, 20.3; IR (pure, cm)^-1)3416，3026，1521，807.

N- (4-cyanophenyl) morpholine¹¹

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(11.5mg, 0.025mmol, 5 mol% Pd), ligand 2(14.8mg, 0.075mmol, 7.5 mol%), NaOt-Bu (68mg, 0.71mmol) and 4-chlorobenzonitrile (69mg, 0.50 mmol). The tube was purged with argon and then DME (0.5mL) and morpholine (53. mu.L, 0.61mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 26 hours, then diluted with EtOAc and passed through celiteFiltered and concentrated in vacuo. Crude product is treatedMaterial was purified by flash chromatography on silica gel to give 91mg (96%) of a brown solid.

Amination with 0.05 mol% Pd the oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(2.3mg, 0.0025mmol, 0.05 mol% Pd), ligand 2(2.9mg, 0.0075mmol, 0.075 mol%) and NaOt-Bu (1.34g, 13.9 mmol). Toluene (10mL), di-n-butylamine (2.00mL, 11.9mmol) and 4-chlorotoluene (1.18mL, 10.0mmol) were added and the mixture was degassed using three freeze-pump-thaw cycles. The reaction vessel was placed under argon, sealed with a teflon screw cap, and stirred in a 100 ℃ oil bath for 20 hours, after which GC analysis showed that the aryl halide had been completely consumed. The reaction mixture was cooled to room temperature, diluted with ether (100mL) and extracted with 1M HCl (3X 100 mL). The combined aqueous acidic layers were basified with 3N NaOH and then extracted with ether (3X 150 mL). The ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated to give 2.01g (95%) of di-n-butyltoluidine 6 as a pale yellow oil.

General procedure for room temperature palladium-catalyzed amination of aryl bromides: the oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(0.005-0.025mmol, 1-5 mol% Pd), ligand 2(0.015-0.075mmol, 1.5-7.5 mol%) and NaOt-Bu (1.4mmol) [ for the amount of Pd and the ligand used refer to Table 1]. The tube waspurged with argon, equipped with a rubber septum, and then DME (0.5mL-1.0mL), aryl bromide (1.0mmol) and amine (1.2mmol) were added via syringe. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 24 hours, then the reaction mixture was diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

2, 6-dimethyl-N- (N-hexyl) aniline

The general procedure was followed using 0.5mmol of aryl bromide and gave 90mg (87%) of a colorless oil:

¹H NMR(300MHz，CDCl₃)δ6.98(d，2H，J＝7.5Hz)，6.79(t，1H，J＝7.5Hz)，2.97(t，2H，J＝7.2Hz)，2.94-2.99(br，1H)，2.28(s，6H)，1.52-1.60(m，2H)，1.28-1.41(m，6H)，0.89(t，3H，J＝6.8Hz)；¹³C NMR(125MHz，CDCl₃) δ 146.5, 129.1, 128.8, 121.5, 48.7, 31.7, 31.2, 26.9, 22.6, 18.5, 14.0; IR (pure, cm)^-1)3384, 2926, 1472, 1256, 1219, 762₁₄H₂₃N: c, 81.89; h, 11.29. found: c, performing phase inversion; h,.

N- (2, 5-dimethylphenyl) morpholine

The general procedure was carried out at a concentration of 2.0M and gave 185mg (95%) of a colorless oil:

¹H NMR(300MHz，CDCl₃)δ7.06(d，1H，J＝7.7Hz)，6.80-6.82(m，2H)，3.84(t，4H，J＝4.6Hz)，2.89(t，4H，J＝4.6Hz)，2.31(s，3H)，2.26(s，3H)；¹³CNMR(125MHz，CDCl₃) δ 151.1, 136.2, 131.0, 129.3, 124.0, 119.7, 67.5, 52.3, 21.1, 17.4; IR (pure, cm)^-1)2955, 2851, 1505, 1242, 1117, 807,analytically calcd C₁₂H₁₇NO: c, 75.35; h, 8.96, found: c, performing phase inversion; h,.

N- (4-carbomethoxyphenyl) morpholine¹⁵

At 80 ℃ except with K₃PO₄Instead of NaOt-Bu, the general procedure used was 89mg (80%) of a colorless solid using 0.5mmol of aryl bromide and EtOAc as the starting solvent (workup solvent):

mp 152-154℃(lit.¹⁵mp 157-160℃).¹H NMR(300MHz，CDCl₃)δ7.94(d，2H，J＝8.6Hz)，6.86(d，2H，J＝8.8Hz)，3.87(s，3H)，3.86(t，4H，J＝4.8Hz)，3.29(t，4H，J＝4.8Hz)；¹³C NMR(125MHz，CDCl₃) δ 167.0, 154.2, 131.2, 120.4, 113.5, 66.6, 51.6, 47.8; IR (pure, cm)^-1)2968, 1698, 1289, 1116, 768 analytically calcd C₁₂H₁₅NO₃: c, 65.14; h, 6.83. found: c, performing phase inversion; h,.

N- (4-acetylphenyl) morpholine¹⁶

At 80 ℃ reaction temperature, except using Pd₂(OAc)₃、K₃PO₄Replace Pd₂(dba)₃1/1Et was used in addition to NaOt-Bu₂O/EtOAc as the starting solvent general procedure gave 169mg (82%) of a light yellow solid:

m.p.93-94℃(lit.¹⁴mp 97-98℃).¹H NMR(300MHz，CDCl₃)δ7.89(d，2H，J＝9.1Hz)，6.87(d，2H，J＝9.1Hz)，3.86(t，4H，J＝4.8Hz)，3.31(t，4H，J＝5.1Hz)，2.54(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 196.4, 154.1, 130.2, 128.1, 113.2, 66.5, 47.5, 26.0; IR (pure, cm)^-1)2972, 1660, 1243, 1119, 818, analytically calculated value C₁₂H₁₅NO₂: c, 70.22; h, 7.37. found: c, 70.31; h, 7.22.

Amination with dicyclohexylphenylphosphine as support ligand. According to the general procedure for aryl chloride catalyzed amination, coupling of 4-chlorotoluene and di-n-butylamine using dicyclohexylphenylphosphine instead of ligand 2 gave 96% conversion (17% GC yield) in 12 hours. In the same time, the reaction with ligand 2 was completed, giving 97% isolated yield of the product. Coupling of 2-bromo-p-xylene and morpholine according to the room temperature method described above, replacing ligand 2 with dicyclohexylphenylphosphine (1.5L/Pd) resulted in the consumption of 2.5% of the starting aryl bromide, with trace products detected (GC). When a 3L/Pd ratio was used, no reaction was observed.

General procedure for room temperature Suzuki coupling of aryl halides: the oven dried resealable Schlenk tube was purged with argon and charged with Pd (OAc)₂(0.02mmol, 2 mol%), ligand 2(0.03mmol, 3 mol%), the boronic acid (1.5mmol) and cesium fluoride (3.0 mmol).The tube was purged with argon and dioxane (3mL) and aryl halide (1.0mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until complete consumption of the starting aryl halide was determined by GC analysis. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

3, 5-Dimethylbiphenyl¹⁷

Use of 1 mol% Pd (OAc)₂And 1.5 mol% ligand 2, the general procedure gave 171mg (94%) of a colorless oil.

¹H NMR(300MHz，CDCl₃)δ7.57(d，2H，J＝6.8Hz)，7.42(t，2H，J＝7.2Hz)，7.31-7.34(m，1H)，7.21(s，2H)，7.00(s，1H)，2.38(s，6H)；¹³C NMR(125MHz，CDCl₃) δ 141.5, 141.3, 138.2, 128.9, 128.6, 127.2, 127.0, 12.5.1, 21.4; IR (pure, cm)^-1)3030, 1602, 849, 760 analytically calcd C₁₄H₁₄: c, 92.26; h, 7.74. found: c, 91.98; h, 8.02.

2, 5, 3' -trimethylbiphenyl¹⁸

General procedure gave 192mg (98%) of a colorless oil, obtained from¹H NMR identification of theThe oil contained 4% 3, 3' -dimethylbiphenyl:

¹H NMR(300MHz，CDCl₃)δ7.25-7.28(m，1H)，7.04-7.16(m，6H)，2.39(s，3H)，2.34(s，3H)，2.23，(s，3H)；¹³C NMR(125MHz，CDCl₃)δ142.1，141.9，137.5,135.0, 132.1, 130.5, 130.2, 129.9, 127.85, 127.80, 127.3, 126.2, 21.4, 20.9, 19.9; IR (pure, cm)^-1)2949, 1451, 811, 703 analytically calculated value C₁₅H₁₅: c, 92.26; h, 7.74. found: c, 92.34; h, 7.66.

4-acetyl-3' -methylbiphenyl¹⁹

General procedure 190mg (90%) of a white solid were obtained:

mp 84-86℃(lit.¹⁹mp92℃).¹H NMR(300MHz，CDCl₃)δ8.02(d，2H，J＝8.5Hz)，7.68(d，2H，J＝8.5Hz)，7.33-7.44(m，3H)，7.20-7.26(m，1H)，2.64(s，3H)，2.43(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 197.6, 145.8, 139.7, 138.5, 135.7, 128.9, 128.8, 127.9, 127.1, 124.3, 26.5, 21.4; IR (pure, cm)^-1)3019, 1683, 1270, 787, analytically calculated value C₁₅H₁₄O: c, 85.68; h, 6.71. found: c, 85.79; h, 6.92

4-Phenylbenzoic acid methyl ester²⁰

The general procedure (except that water was used as the aqueous starter instead of 1M aqueous NaOH) gave 193mg (91%) of a white solid:

mp 113℃(lit.²⁰mp 117-118℃).¹H NMR(300MHz，CDCl₃)δ8.11(d，2H，J＝8.3Hz)，7.61-7.68(m，4H)，7.39-7.49(m，3H)，3.94(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 166.9, 145.5, 139.9, 130.0, 128.8, 128.1, 127.2, 126.9, 52.0; IR (pure, cm)^-1)2945, 1710, 1270, 1112, 749 analytically calculated value C₁₄H₁₃O₂: c, 78.85; h, 6.14. found: c, 79.04; h, 6.16.

4-Hexylanisole²¹

The oven dried resealable Schlenk tube was capped with a rubber septum, cooled under an argon purge, charged with 1-hexane (0.19mL, 1.5mmol) and cooled to 0 ℃. A solution of 9-BBN in THF (3mL, 1.5mmol, 0.5M) was added and the flask was stirred at 0 deg.C for 15 minutes, then warmed to room temperature and stirred for 5 hours. 4-chloroanisole (0.12mL, 1.0mmol) was added, the septum removed, and palladium acetate (4.4mg, 0.02mmol, 2 mol%), ligand 2(11.9mg, 0.03mmol, 3 mol%), and cesium fluoride (456mg, 3.0mmol) were added under argon flow. The septum was placed and the flask was purged with argon for 30 seconds. Dioxane (2mL) was added, the septum was removed, the tube was sealed with a teflon screw cap, and the mixture was stirred at room temperature for 2 minutes. The reaction mixture was then heated to 50 ℃ over 22 hours with stirring, at which time GC analysis showed complete consumption of the aryl chloride. The mixture was cooled to room temperature, diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M aqueous NaOH (20mL), the layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to give 170mg (89%) of a colorless oil:

¹H NMR(300MHz，CDCl₃)δ7.09(d，2H，J＝8.8Hz)，6.82(d，2H，J＝8.6Hz)，3.78(s，3H)，2.54(t，2H，J＝7.5Hz)，1.54-1.60(m，2H)，1.28-1.35(m，6H)，0.88(t，3H，J＝6.8Hz)；¹³C NMR(125MHz，CDCl₃) δ 157.6, 135.0, 129.2, 113.6, 55.2, 35.0, 31.73, 31.70, 28.9, 22.6, 14.1; IR (pure, cm)^-1)2926, 1513, 1243, 1038, 822 analytically calcd C₁₃H₂₀O: c, 81.20; h, 10.48. found: c, 81.19; h, 10.62.

For K₃PO₄General procedure for the accelerated Suzuki coupling of aryl chlorides: the oven dried resealable Schlenk tube was purged with argon and charged with Pd (OAc)₂(0.01mmol, 0.5 mol%), ligand 2(0.015mmol, 0.75 mol%), the boronic acid (3.0mmol) and potassium phosphate (4.0 mmol). The tube was purged with argon through rubberDioxane (6mL) and 4-chlorotoluene (2.0mmol) were added to the gum spacer. The spacers were removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes and then heated to 100 ℃ with stirring until complete consumption of the starting aryl chloride was determined by GC analysis. The reaction mixture was then cooled to room temperature, diluted with ether (20mL) and poured into aseparatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

4-methoxybiphenyl²²

General procedure 347mg (94%) of a white solid were obtained:

mp 83-84℃(lit.²²mp87℃)；¹H NMR(250MHz，CDCl₃)δ7.52-7.58(m，4H)，7.42(t，2H，J＝7.8Hz)，7.26-7.38(m，1H)，6.97(d，2H，J＝6.7Hz)，3.86(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 159.1, 140.8, 133.7, 128.7, 128.1, 126.7, 126.6, 114.2, 55.3; IR (pure, cm)^-1)3003, 1251, 1034, 834, 760 analytically calcd C₁₃H₁₂O: c, 84.75; H.6.57. measured value: c, 85.06; h, 6.72.

4-methylbiphenyl²³

General procedure 319mg (95%) of a white solid were obtained:

mp 44-46℃(lit，²³mp49-50℃)；¹H NMR(250MHz，CDCl₃)δ7.57(d，2H，J＝8.8Hz)，739-7.51(m，4H)，7.23-7.35(m，3H)，2.40(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 141.2, 138.4, 136.9, 129.4, 128.7, 126.94, 126.92, 21.0; IR (pure, cm)^-1)3030, 1486, 822, 753 analytically calcd value C₁₃H₁₂: c, 92.81; h, 7.19. found: c, performing a chemical reaction on the mixture to obtain a reaction product,92.86；H，7.15.

4-methyl-2' -methoxybiphenyl²⁴

1 mol% Pd (OAc) at 1mmol scale₂1.5

mol% ligand

2 and 3 equivalents of CsF instead of K₃PO₄The general procedure was followed to give 196mg (99%) of a white solid, mp 74-75 deg.C (lit,²⁴mp 70-72℃)；¹H NMR(250MHz，CDCl₃)δ7.42(d，2H，J＝8.1Hz)，7.21-7.33(m，4H)，7.16-7.04(m，2H)，3.81(s，3H)，2.39(s，3H)；¹³C NMR(125MHz，CDCl₃) δ 156.5, 136.5, 135.6, 130.7, 129.4, 128.6, 128.3, 120.8, 111.2, 55.5, 21.2; IR (pure, cm)^-1)2964, 1227, 1023, 757, analytically calcd C₁₄H₁₄O: c, 84.81; h, 7.12. found: c, 84.94; h, 7.36.

Suzuki coupling using dicyclohexylphenylphosphine as the truncation ligand. Two coupling reactions of 4-chlorotoluene and phenylboronic acid were carried out using the general method of Suzuki coupling described above, replacing ligand 2 with dicyclohexylphenylphosphine (2L/Pd). The reaction was performed at room temperature with CsF as base for 10% conversion (50% GC yield) after two days, and at 100 ℃ with K₃PO₄As base a 27% conversion (18% GC yield) was performed in two days.

2-methyl-4- (3, 5-xylyl) -3-pentanone

The oven dried resealable Schlenk tubes were rinsed with NaHMDS (238mg, 1.3mmol) in a Vacuum atmosphers dry box under nitrogen atmosphere. The tube was fitted with teflon screw caps and removed from the dry box. Removing the screw cap and charging Pd under argon flow₂(dba)₃(13.7mg, 0.015mmol, 3 mol% Pd) and ligand 2(14.1mg, 0.036mmol, 3.6 mol%). The tube was capped with a rubber septum and toluene (3mL) was added with stirring. The flask was then treated with 5-bromo-m-xylene (0.135mL, 1.0 m)mol), 2-methyl-3-pentanone (0.15mL, 1.2mmol) and an additional amount of toluene (3 mL). The spacer was replaced with a teflon screw cap and the reaction mixture was stirred at room temperature for 22 hours until complete consumption of the starting aryl bromide was determined by GC analysis. The reaction was quenched with 5mL of saturated aqueous NH₄The Cl was quenched, diluted with ether (20mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 163mg (80%) of a colorless oil. GC and NMR analysis showed that the material obtained was a mixture of the desired product and of a regioisomer containing an aryl group in the 2-position of the ketone (46/1 ratio by GC analysis; 40/1 ratio by GC analysis)¹H NMR analysis). MNR data were derived from the primary products only.

¹H NMR(250MHz，CDCl₃)δ6.88(s，1H)，6.81(s，2H)，3.83(q，1H，J＝6.9Hz)，2.68(p，1H，J＝6.9Hz)，2.29(s，6H)，1.34(d，3H，J＝6.9Hz)，1.07(d，3H，J＝7.0Hz)，0.92(d，3H，J＝6.6Hz）；¹³C NMR(125MHz，CDCl₃) δ 214.7, 140.7, 138.3, 128.6, 125.7, 50.9, 39.0, 21.2, 19.3, 18.2, 18.1; IR (pure, cm)^-1)2972, 1710, 1101, 849 analytically (for mixtures) calculated value C₁₄H₂₀O: c, 82.3; h, 9.87. found: c, 82.09; h, 9.85.

1, 1-bis (4-methylphenyl) -3-methyl-2-butanone

The dried Schlenk tube was cooled and charged with Pd under an argon purge₂(dba)₃(13.7mg, 0.015mmol, 3 mol% Pd), ligand 2(14.1mg, 0.036mmol, 3.6 mol%) and NaOtBu (211mg, 2.2 mmol). The flask was purged with argon and toluene (3mL) was added with stirring. The flask was then filled with 4-chlorotoluene (0.24mL, 2.0mmol), 3-methyl-2-butanone (0.105mL, 1.0mmol) and an additional amount of toluene (3 mL). The reaction mixture was stirred at room temperature for 2 minutes and then heated to 80 ℃ over 22 hours with stirring, at which time it was GCAnalysis confirmed complete consumption of the starting aryl chloride. The reaction mixture was cooled to room temperature and saturated aqueous NH was used₄Cl (5mL) was quenched, diluted with ether (20mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (10 mL). The combined organic fractions were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel to give 210mg (79%) of a white solid:

mp 48-51℃；¹H NMR(300MHz，CDCl₃)δ7.00-7.18(m，8H)，5.22(s，1H)，2.79(p，1H，J＝6.8Hz)，2.31(s，6H)，1.10(d，6H，J＝6.8Hz)；¹³C NMR(125MHz，CDCl₃) δ 212.3, 136.6, 135.8, 129.24, 129.16, 128.9, 128.7, 61.4, 40.7, 21.0, 18.6; IR (pure, cm)^-1)2972, 1718, 1513, 1038, 803 analytically calculated value C₁₄H₂₀O: c, 85.67; h, 8.32. found: c, 86.02; h, 8.59.

Reference to the document supporting example 1

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(3)Zhang，X.；Mashima，K.；Koyano，K.；Sayo，N.；Kumobayashi，H.；Akutagawa，S.；Takaya，H.J.Chem.Soc.Perkin Trans.1 1994，2309-2322.

(4)Miyashita，A.；Takaya，H.；Souchi，T.；Noyori，R.Tetrahedron 1984，40，1245-1253.

(5)Hegedus，L.S.in Organometallics in Synthesis Schlosser，M，Ed.，John Wiley andSons，West Sussex，England，1994，p 448.

(6)Wolfe，J.P.；Buchwald，S.L.J.Org.Chem.1996，61，1133-1135.

(7)Marcoux，J.-F.；Wagaw，S.；Buchwald，S.L.J.Org.Chem.1997，62，1568-1569.

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(9)Wolfe，J.P.；Buchwald，S.L.J.Am.Chem.Soc.1996，118，7215-7216.

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(11)Wolfe，J.P.；Buchwald，S.L.J.Org.Chem.1997，62，1264-1267.

(12)Lauer，M.；Wulff，G.J.Organomet.Chem.1983，256，1-9.

(13)Abe，M.；Takahashi，M.Synthesis 1990，939-942.

(14)Watanabe，Y.；Tsuji，Y.；Ige，H.；Ohsugi，Y.；Ohta，T.J.Org.Chem.1984，49，3359-3363.

(15)Behringer，H.；Heckmaier，P.Chem.Ber.1969，102，2835-2850.

(16)Kotsuki，H.；Kobayashi，S.；Matsumoto，K.；Suenaga，H.；Nishizawa，H.Synthesis1990，1147-1148.

(17)H_felinger，G.；Beyer，M.；Burry，P.；Eberle，B.；Ritter，G.；Westermayer，G，；Westermayer，M.Chem.Ber.1984，117，895-903.

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(20)Barba，I.；Chinchilla，R.；Gomez，C.Tetrahedron 1990，46，7813-7822.

(21)Skraup，S.；Nieten，F.Chem.Ber.1924，1294-1310.

(22)Darses，S.；Jeffery，T.；Brayer，J.-L.；Demoute，J.-P.；Genet，J.-P.Bull.Soc.Chim.Fr.1996，133，1095-1102.

(23)Rao，M.S.C.；Rao，G.S.K.Synthesis 1987，231-233.

(24)Hatanaka，Y.Goda，K.-i.；Okahara，Y.；Hiyama，T.Tetrahedron 1994，50，8301-8316.

Example 2

Synthesis of N- (2, 5-dimethylphenyl) -N-methylaniline.

The dried test tube was purged with argon and charged with Pd₂(dba)₃(4.6mg, 0.005mmol, 1.0 mol% Pd), ligand 2[ example 1](6.0mg, 0.015mmol, 1.5 mol%) and NaOt-Bu (135mg, 1.40 mmol). The tube was fitted with a septum and toluene (2.0mL), N-methylaniline (135. mu.L, 1.25mmol) and 2-chloro-p-xylene (135. mu.L, 1.01mmol) were added. The mixture was stirred at 80 ℃ for 13 h, then cooled to room temperature, diluted with ether (20mL), filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 202mg (95%) of a colorless oil.

Example 3

Synthesis of di-n-butyl-p-toluidine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(2.3mg, 0.0025mmol, 0.05 mol% Pd), ligand 2[ example 1]](2.9mg, 0.0075mmol, 0.075 mol%) and NaOt-Bu (1.34g, 13.9 mmol). Toluene (10mL), di-n-butylamine (2.00mL, 11.9mmol) and 4-chlorotoluene (1.18mL, 10.0mmol) were added and the mixture was degassed using three freeze-pump-thaw cycles. Placing the reaction vessel in an argon atmosphereNext, the vessel was sealed with a Teflon screw cap and stirred at 100 ℃ for 20 hours, after which GC analysis showed that the aryl halide had been completely consumed. The reaction mixture was cooled to room temperature, diluted with ether (100mL) and extracted with 1M HCl (3X 100 mL). The combined aqueous acid phases were basified with 3M NaOH and then extracted with ether (3X 150 mL). The ether extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.01g (95%) of a pale yellow oil.

Example 4

Synthesis of N- (4-cyanophenyl) morpholine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(11.5mg, 0.025mmol, 5 mol% Pd), ligand 2[ example 1](14.8mg, 0.075mmol, 7.5 mol%), NaOt-Bu (68mg, 0.71mmol) and 4-chlorobenzonitrile (69mg, 0.50 mmol). The tube was purged with argon and then DME (0.5mL) and morpholine (53. mu.L, 0.61mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 26 hours. The reaction was diluted with EtOAc (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 91mg (96%) of a brown solid.

Example 5

Synthesis of N- (2, 5-dimethylphenyl) morpholine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(13.9mg, 0.015mmol, 3.0 mol% Pd), ligand 2[ example 1](17.9mg，0.045mmol, 4.5 mol%) and NaOt-Bu (140mg, 1.4 mmol). The tube was purged with argon, a rubber septum was installed, and then DME (0.5mL), 2-bromo-p-xylene (140 μ L, 1.01mmol) and morpholine (105 μ L, 1.2mmol) were added via syringe. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 185mg (95%) of a colorless oil.

Example 6

Synthesis of N- (4-carbomethoxyphenyl) morpholine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(2.3mg, 0.0025mmol, 1.0 mol% Pd), ligand 2[ example 1]](3.0mg，0.0076mmol，1.5mol％)、K₃PO₄(150mg, 0.71mmol) and methyl 4-bromobenzoate (108mg, 0.50 mmol). The tube was purged with argon and fitted with a rubber septumThe plate was then charged with DME (1.0mL) and morpholine (55. mu.L, 0.63 mmol). The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at 80 ℃ for 24 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 89mg (80%) of a colorless solid.

Example 7

Synthesis of N-benzyl-p-toluidine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(4.6mg，0.005mmol，1.0mol％Pd)、Cy-BINAP(9.6mg，0.015mmol，1.5mol%) and NaOtBu (135mg, 1.4 mmol). The tube was purged with argon and charged with toluene (2mL), 4-chlorotoluene (0.12mL, 1.0mmol) and benzylamine (0.165mL, 1.5 mmol). The mixture was heated to 100 ℃ with stirring until complete consumption of the starting aryl chloride was confirmed by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 177mg (90%) of a light yellow oil.

Example 8

Synthesis of 3, 5-dimethylbiphenyl by Suzuki coupling

The oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1 mol%), ligand 2[ example 1](5.9mg, 0.015mmol, 1.5 mol%), phenylboronic acid (183mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was purged with argon and dioxane (3mL) and 5-bromo-m-xylene (0.135 μ L, 1.0mmol) were added through the rubber septum. The spacer was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until complete consumption of the starting aryl bromide was confirmed by GC analysis. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 171mg (94%) of a colorless oil.

Example 9

Synthesis of 4-methylbiphenyl by Suzuki coupling

The oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (4.4mg, 0.02mmol, 2 mol% Pd), ligand 2[ example 1](11.9mg, 0.03mmol, 3 mol%), phenylboronic acid (183mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was purged with argon and dioxane (3mL) and 4-chlorotoluene (0.12mL, 1.0mmol) were added through the rubber septum. The spacers were removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until complete consumption of the starting aryl chloride was confirmed by GC analysis. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to yield 157mg (93%) of a glassy solid.

Example 10

Synthesis of 3-methyl-4' -acetylbiphenyl by Suzuki coupling

The oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (4.4mg, 0.02mmol, 2 mol%), ligand 2[ example 1](11.9mg, 0.03mmol, 3 mol%), 3-methylphenylboronic acid (204mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was purged with argon and dioxane (3mL) and 4-chloroacetophenone (0.13mL, 1.0mmol) were added through the rubber septum. The spacers were removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until complete consumption of the starting aryl chloride was confirmed by GC analysis. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 195mg (93%) of a white solid.

Example 11

Synthesis of 4-methoxybiphenyl by Suzuki coupling

The oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (2.2mg, 0.01mmol, 0.5 mol%), ligand 2[ example 1](5.9mg, 0.015mmol, 0.75 mol%), phenylboronic acid (366mg, 3.0mmol) and potassium phosphate (850mg, 4.0 mmol). The tube was purged with argon and dioxane (6mL) and 4-chloro anisole (0.24mL, 2.0mmol) were added through the rubber septum. The spacers were removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes and then heated to 100 ℃ with stirring until complete consumption of the starting aryl chloride was confirmed by GC analysis. The reaction mixture was then diluted with ether (40mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (40mL) and the layers were separated. The aqueous layer was extracted with ether (40mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 347mg (94%) of a white solid.

Example 12

Synthesis of 2-amino-2 '-bromo-1, 1' -binaphthyl benzophenone imine

The dried 100mL round bottom flask was equipped with a reflux condenser, purged with argon and charged2.2 '-dibromo-1, 1' -binaphthyl (5.0g, 12.1mmol), benzophenone imine (2.9g, 15.7mmol), NaOt-Bu (1.7g, 18.0mmol), Pd₂(dba)₃(110mg, 0.12mmol), bis (2- (diphenylphosphino) phenyl) ether (129mg, 0.24mmol) and toluene (50 mL.) the mixture was stirred at 100 ℃ for 18 h, then cooled to room temperature and 2/3 solvent was removed under reducing pressure, ethanol (25mL) and water (3mL) were added to the resulting mixture, the yellow crystals were collected on a B ü chner funnel and washed with ethanol (10mL) to give 5.7g (92%) of the crude which was used in the examples below without further purification.

Example 13

Synthesis of 2-amino-2 '-bromo-1, 1' -binaphthyl

The crude imine from example 12 (3.0g, 5.9mmol) was suspended in dichloromethane (100mL) in a 300mL round bottom flask. Concentrated hydrochloric acid (1.5mL, 17.6mmol) was added to the suspension, which became homogeneous within 15 minutes. The mixture was stirred at room temperature for 18 hours, during which time a precipitate formed. The mixture was then treated with 1M NaOH (25mL) and the layers separated. The aqueous layer was extracted with an additional amount of dichloromethane (10 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 1.5g (73%) of colorless crystals.

Example 14

Synthesis of 2-N, N-dimethylamino-2 '-bromo-1, 1' -binaphthyl

A20 mL round-bottomed flask was charged with the amine of example 13 (480mg, 1.4mmol), methyl iodide (0.25mL, 4.2mmol), sodium carbonate (318mg, 3.0mmol), and DMF (8mL), then purged with argon. The mixture was heated to 50 ℃ and stirred until the starting material was completely consumed. The reaction mixture was diluted with ether (5mL) and water (1mL) and passed through a plug of silica gel. The filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 473mg (91%) of colorless crystals.

Example 15

Synthesis of 2-N, N-dimethylamino-2 '-diphenylphosphino-1, 1' -binaphthyl (26)

A dried 20mL round bottom flask was charged with the bromide of example 14 (300mg, 0.8mmol) and THF (8 mL). The mixture was purged with argon and cooled to-78 deg.C, then n-butyllithium (0.6mL, 0.9mmol) was added dropwise. The solution was stirred at-78 ℃ for 45 minutes, then chlorodiphenylphosphine (229mg, 1.0mmol) was added dropwise. The reaction was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred for 18 hours. Saturated aqueous ammonium chloride (2mL) was added and the reaction mixture was extracted with diethyl ether (2X 10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 340mg (88%) of colorless crystals.

Example 16

Synthesis of 2-N, N-dimethylamino-2 '-dicyclohexylphosphino-1, 1' -binaphthyl (27)

A dried 20mL round bottom flask was charged with the bromide of example 14 (600mg, 1.6mmol) and THF (16 mL). Themixture was purged with argon and cooled to-78 deg.C, then n-butyllithium (1.1mL, 1.8mmol) was added dropwise. The solution was stirred at-78 ℃ for 45 minutes, then chlorodicyclohexylphosphine (484mg, 2.1mmol) was added dropwise. The reaction was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred for 18 hours. Saturated aqueous ammonium chloride (2mL) was added and the reaction mixture was extracted with diethyl ether (2X 10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from dichloromethane and methanol to yield 623mg (79%) of 27 as colorless crystals.

Example 17

Synthesis of N- (4-methoxyphenyl) pyrrolidine

The dried test tube is filled with Pd₂(dba)₃(4.5mg, 0.005mmol), 27(7.4mg, 0.015mmol), 4-chloroanisole (140mg, 0.98mmol), pyrrolidine (85mg, 1.2mmol), NaOt-Bu (135mg, 1.4mmol), toluene (2mL) and argon purge. The mixture was heated to 80 ℃ and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with ether (5mL), filtered through a plug of celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 165mg (95%) of the title product as colorless crystals.

Example 18

Synthesis of N-benzyl-p-toluidine

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(4.6mg, 0.005mmol, 1.0 mol% Pd), 27(7.4mg, 0.015mmol, 1.5 mol%) and NaOt-Bu (135mg, 1.4 mmol). The tube was purged with argon, toluene (2mL), 4-chlorobenzenetoluene (0.12mL, 1.0mmol) and benzylamine (0.165mL,1.5 mmol). The tube was sealed with a teflon screw cap instead of a septum and the mixture was heated to 100 ℃ with stirring until complete consumption of the starting aryl chloride was confirmed by GC analysis. A small amount of diarylated benzylamine was detected in the crude reaction mixture (product/diarylated benzylamine GC ratio 16/1). The reaction mixture was cooled to room temperature, diluted with ether (20mL) and extracted with 1M HCl (5X 40 mL). The organic phase was discarded and the combined aqueous extracts were acidified to pH 14 with 6M NaOH and extracted with diethyl ether (4X 50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 175mg (89%) of a pale yellow oil.

Example 19

Synthesis of N- (4-methylphenyl) indole

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(11.2mg, 0.012mmol, 2.5 mol% Pd), ligand 2[ example 1](14.4mg，0.036mmol，7.5 mol%), NaOt-Bu (130mg, 1.35mmol) and indole (115mg, 0.98 mmol). The tube was purged with argon and then toluene (1.0mL) and 4-bromotoluene (120 μ L, 0.98mmol) were added through the rubber septum. The septum was removed, the tube sealed with a teflon screw cap and the mixture stirred at 100 ℃ for 21 hours. The reaction mixture was then diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 191mg (94%) of a colorless oil.

Example 20

Synthesis of N- (4-fluorophenyl) indole

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(11.5mg, 0.013mmol, 5 mol% Pd), ligand 2[ example 1](14.8mg, 0.038mmol, 7.5 mol%), NaOt-Bu (68mg, 0.71mmol) and indole (60mg, 0.51 mmol). The tube was purged with argon and then toluene (0.5mL) and 1-bromo-4-fluorobenzene (55 μ L, 0.50mmol) were added through a rubber septum. The septum was removed, the tube sealed with a teflon screw cap and the mixture stirred at 100 ℃ for 36 hours. The reaction mixture was then diluted with ether (20mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 81mg (77%) of a colorless oil.

Example 21

Synthesis of N- (4-methylphenyl) indole

The oven dried resealable Schlenk tube was purged with argon and charged with Pd₂(dba)₃(11.6mg, 0.012mmol, 5 mol% Pd), ligand 2[ example 1](11.0mg，0.028mmol，5.5mol％)、Cs₂CO₃(230mg, 0.75mmol) and indole (60mg, 0.51 mmol). The tube was purged with argon and then toluene (1.0mL) and 4-chlorotoluene (60 μ L, 0.51mmol) were added through a rubber septum. Removing the spacers, the tube being sealed with a Teflon screw capAnd the mixture was stirred at 100 ℃ for 24 hours. The reaction was then diluted with ether (20mL), filtered through celite and concentrated in vacuo. Subjecting the crude product to flash chromatography on silica gelPurification by chromatography gave 94mg (89%) of a colorless oil.

Example 22

Synthesis of 2-bromo-2 '-methoxy-1, 1' -biphenyl

2-Bromoiodobenzene (640. mu.L, 5.0mmol) was added to Pd (PPh) under argon at room temperature₃)₄(305mg, 0.26mmol) in DME (100 mL). After 5 minutes at room temperature, a solution of 2-methoxyphenylboronic acid (760mg, 5.0mmol) in ethanol (2mL) was added, followed by aqueous Na₂CO₃(2.0M, 5mL, 10 mmol). The reaction vessel was fitted with a reflux condenser and heated to reflux under argon atmosphere for 22.5 hours. The reaction mixture was then cooled to room temperature and filtered through celite. The filter box was washed with ether and water and the filtrate was concentrated in vacuo. The aqueous residue obtained is diluted with brine and extracted with diethyl ether. Drying (MgSO)₄) Ether layer, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel to give 823mg (63%) of a colorless oil.

Example 23

Synthesis of 2-dicyclohexylphosphino-2 '-methoxy-1, 1' -biphenyl

A solution of example 1(535mg, 2.03mmol) in THF (20mL) was cooled to-78 deg.C under argon, then n-BuLi (1.6M in hexane, 1.35mL, 2.16mmol) was added dropwise. After 2.5 h at-78 deg.C, a solution of chlorodicyclohexylphosphine (570mg, 2.45mmol) in THF (3mL) was added over 10 min. The reaction mixture was then warmed to room temperature overnight and then saturated aqueous NaHCO was used₃Quenched and concentrated in vacuo. The obtained water contentThe suspension was extracted with diethyl ether (2X 50mL) and dried (Na)₂SO₄) The combined extract layers were filtered and concentrated in vacuo. The resulting crude solid was recrystallized from ethanol to yield 420mg (54%) of a white solid.

Example 24

Synthesis of N- (4-methylphenyl) indole

The dried test tube was purged with argon, and then charged with 2-dicyclohexylphosphino-2 '-methoxy-1, 1' -biphenyl (14.5mg, 0.038mmol, 7.5 mol%) and Pd₂(dba)₃(11.6mg，0.013mmol, 5.0 mol% Pd). Toluene (1.0mL), indole (71mg, 0.61mmol), 4-chlorotoluene (60mL, 0.51mmol) and NaOt-Bu (70mg, 0.73mmol) were then added. The tube was fitted with a septum, purged with argon and heated at 100 ℃ for 28 hours. The reaction mixture was cooled to room temperature, diluted with ether (20mL), filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 99mg (94%) of a colorless oil.

Example 25

Synthesis of 2- (di-tert-butylphosphino) -biphenyl

A solution of 2-bromobiphenyl (5.38g, 23.1mmol) and a little iodine crystals in 40mL THF was heated to reflux with magnesium turnings (617mg, 25.4mmol) for 2 h. The heat was temporarily removed to allow addition of cuprous chloride (2.40g, 24.2mmol) followed by chlorodi-tert-butylphosphine. Heating was continued for another 8 hours. The reaction mixture was then removed from the heater and cooled to room temperature. The reaction mixture was poured onto 200mL of 1: 1 hexane/ether. The suspension was filtered and the filter cake was washed with 60mL of hexane. The solid was partitioned between 150mL of 1: 1 hexane/ethyl acetate and 60mL of concentrated ammonium hydroxide in 100mL of water. The organic layer was washed with 100mL brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The white solid was recrystallized from 30mL MeOH to give 2- (di-tert-butylphosphino) biphenyl (4.01g, 58%) as white crystals. A second crop of product was obtained by recrystallization from 50mL MeOH and 25mL water (464mg, 67%).

Example 26

General method for determining the effect of various additives on the preparation of 4-methylbiphenyl by Suzuki coupling

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-tert-butylphosphino) biphenyl (4.5mg, 0.015mmol, 1.5 mol%), phenylboronic acid (183mg, 1.5mmol), additive (3.0mmol), and 4-chlorotoluene (0.12mL, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (2mL) was added through a rubber septum. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (30mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20mL), followed by brine (20 mL). The organic layer was analyzed by GC to give the results of the following table.

Conversion of additive

Cesium fluoride 55%

62 percent of potassium fluoride

Potassium carbonate 10%

Potassium phosphate 38%

Sodium acetate 0%

Example 27

Using K₃PO₄Synthesis of 4-tert-butylbiphenyl with 0.1 mol% Pd as a base

The oven dried resealable Schlenk tube was evacuated and purged with argonThe gas was back-filled with phenylboronic acid (183mg, 1.5mmol) and potassium phosphate (425mg, 2.0 mmol). The tube was evacuated and back-filled with argon, and DMF (1.5mL) and 1-bromo-4-tert-butylbenzene (0.17mL, 1.0mmol) were added through a rubber septum. The independent flask is filled with Pd₂(dba)₃(4.6mg, 0.005mmol), 2- (di-tert-butylphosphino) biphenyl (4.5mmol, 0.015mmol) and DME (1 mL). The reaction mixture was stirred at room temperature for 1 minute, then 100. mu.L of the solution (0.1 mol% Pd, 0.15 mol% 2- (di-tert-butylphosphino) biphenyl) was added to a Schlenk tube, followed by THF (1.5 mL). The spacer was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes and then heated to 80 ℃ with stirring until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 199mg (95%) of a glassy solid.

Example 28

Synthesis of 4-tert-butylbiphenyl with 0.05 mol% Pd using CsF as base

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with phenylboronic acid (183mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1.5mL) and 1-bromo-4-tert-butylbenzene (0.17mL, 1.0mmol) were added through a rubber septum. The independent flask is filled with Pd₂(dba)₃(4.6mg, 0.005mmol), 2- (di-tert-butylphosphino) biphenyl (4.5mmol, 0.015mmol) and THF (1 mL). The mixture was stirred at room temperature for 1 minute, then 50. mu.L of the solution (0.05 mol% Pd, 0.075 mol% 2- (di-tert-butylphosphino) biphenyl) was added to a Schlenk tube, followed by additionTHF (1.5mL) was added. The spacer was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 minutes and then heated to 80 ℃ with stirring until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was diluted with diethyl ether (20mL)And poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to yield 202mg (96%) of a glassy solid.

Example 29

Optimized synthesis of 4-methylbiphenyl using KF

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 4-chlorotoluene (0.12mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with 1.0M NaOH (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 158mg (94%) of the title compound.

Example 30

Synthesis of 2-cyanomethylbiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 2-chlorobenzyl cyanide (152mg, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with 1.0M NaOH (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 178mg (92%) of the title compound.

Example 31

Synthesis of 4-carbomethoxy-3' -acetylbiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged withpalladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), 3-acetylphenylboronic acid (246mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol) and methyl-4-chlorobenzoate (171mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 229mg (90%) of the title compound.

Example 32

Synthesis of 4-cyanobiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol), and 4-chlorobenzonitrile (136mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extractedwith ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 159mg (89%) of the title compound.

Example 33

Synthesis of 4-formyl-4' -ethoxy biphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (1.1mg, 0.005mmol, 0.5 mol%), 2- (di-t-butylphosphino) biphenyl (3.0mg, 0.01mmol, 1.0 mol%), 4-ethoxyphenylboronic acid (249mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol) and 4-bromobenzaldehyde (185mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 203mg (90%) of the title compound.

Example 34

Synthesis of 4-hydroxybiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol), and 4-bromophenol (173mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to yield 154mg (91%) of the title compound.

Example 35

Synthesis of 2-hydroxymethyl biphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol), and 2-bromobenzyl alcohol (187mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to give 153mg (83%) of the title compound.

Example 36

Synthesis of 2, 5-dimethylbiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 2-bromo-p-xylene (0.138mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to yield 149mg (82%) of the title compound.

Example 37

Synthesis of 4-methoxybiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.002mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 4-chloroanisole (0.123mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to yield 176mg (96%) of the title compound.

Example 38

Synthesis of N-acetyl-4-aminobiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol), and 4' -bromoacetanilide (214mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to give 182mg (86%) of the title compound.

Example 39

Synthesis of 4-nitrobiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), potassium fluoride (174mg, 3.0mmol), and 1-chloro-4-nitrobenzene (158mg, 1.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silicagel to give 196mg (98%) of the title compound.

Example 40

Synthesis of 2, 6-dimethylbiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.002mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 2-bromo-m-xylene (0.144mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at 65 ℃ until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to give 144mg (79%) of the title compound.

EXAMPLE 41

Synthesis of 2-methoxy-4' -methyl biphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), 2-methoxyphenylboronic acid (228mg, 1.5mmol) and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 4-chlorotoluene (0.144mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was stirred at 65 ℃ until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL), filtered through celite and concentrated. The crude material was purified by flash chromatography on silica gel to yield 188mg (95%) of the title compound.

Example 42

Synthesis of 2-methoxy-2' -acetylbiphenyl

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), 2-methoxyphenylboronic acid (228mg, 1.5mmol) and potassium phosphate (425mg, 2.0 mmol). The tube was evacuated and back-filled with argon and toluene (3mL) and 2' -chloroacetophenone (0.13mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was heated to 65 ℃ with stirring until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 201mg (89%) of the title compound.

Example 43

Synthesis of 3- (3-acetylphenyl) pyridine

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.02mmol, 2.0 mol%), 3-acetylphenylboronic acid (246mg, 1.5mmol) and potassium fluoride (173mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 3-chloropyridine (0.095mL, 1.0mmol) were added through a rubber septum. The tube was sealed with a teflon screw cap and the reaction mixture was heated to 50 ℃ with stirring until the starting aryl chloride was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 181mg (92%) of the title compound.

Example 44

Synthesis of 4-acetylbiphenyl from aryl chloride using 0.02 mol% Pd

The oven dried resealable Schlenk tube was evacuated and back filled with argon and charged with phenylboronic acid (228mg, 1.5mmol) and potassium phosphate (425mg, 2.0 mmol). The tube was evacuated and back-filled with argon and toluene (1.5mL) and 4-chloroacetophenone (0.13mL, 1.0mmol) were added through a rubber septum. Palladium acetate (2.2mg, 0.01mmol) and 2- (di-tert-butylphosphino) biphenyl (6.0mg, 0.02mmol) were dissolved in 5mL THF in a round-bottomed flask under argon atmosphere. A portion of this solution (100. mu.L, 0.0002mmol Pd, 0.02 mol% Pd) was added to the reaction mixture through a rubber septum, followed by toluene (1.5 mL). The tube was sealed with a teflon screw cap and the reaction mixture was heated to 100 ℃ with stirring until the starting aryl chloride was identified by GC analysis as having been completelyconsumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 178mg (91%) of the title compound.

Example 45

Synthesis of 4-acetylbiphenyl from aryl bromide using 0.000001 mol% Pd

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with phenylboronic acid (228mg, 1.5mmol), potassium phosphate (425mg, 2.0mmol) and 4-bromoacetophenone (199mg, 1.0 mmol). The tube was evacuated and back-filled with argon and toluene (1.5mL) was added through the rubber septum. Palladium acetate (4.5mg, 0.02mmol) and 2- (di-tert-butylphosphino) biphenyl (12.0mg, 0.04mmol) were dissolved in 20mL THF in a round-bottomed flask in a nitrogen-filled glove box (glovebox) under argon atmosphere. A portion of this solution (10. mu.L, 0.00001mmol Pd, 0.001 mol% Pd) was added to a second flask containing 10mL THF. A portion of this solution (10. mu.L, 0.00000001mmol Pd, 0.000001 mol% Pd) was added to the reaction mixture through a rubber septum followed by toluene (1.5 mL). The tube was sealed with a teflon screw cap and the reaction mixture was heated to 100 ℃ with stirring until the starting aryl bromide was identified by GC analysis as having been completely consumed. The reaction mixture was then diluted with ether (30mL) and poured into a separatory funnel. The mixture was washed with water (20mL) and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 176mg (90%) of the title compound.

Example 46

Optimized synthesis of 2-acetylbiphenyl using potassium fluoride

The oven dried Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (4.5mg, 0.02mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (11.9mg, 0.040mmol, 2.0 mol%), phenylboronic acid (366mg, 3.0mmol) and potassium fluoride (349mg, 6.0 mmol). The tube was evacuated and back-filled with argon, and THF (2mL) and 2-chloroacetophenone (0.26mL, 2.0mmol) were added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis to have been completely consumed. The reaction mixture was then diluted with ethyl acetate (30mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL). The organic layer was washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 369mg (94%) of the title compound.

Example 47

Optimized synthesis of 2-formyl-4' -diphenylketiminate biphenyl using potassium fluoride

The oven dried Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (4.5mg, 0.02mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (11.9mg, 0.040mmol, 2.0 mol%), 4-diphenylketiminate phenyl bromide (672mg, 2.0mmol), 2-formylphenylboronic acid (450mg, 3.0mmol) andpotassium fluoride (349mg, 6.0 mmol). The tube was evacuated and back-filled with argon and THF (2mL) was added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis to have been completely consumed. The reaction mixture was then diluted with ethyl acetate (30mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL). The organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 647mg (90%) of the title compound.

Example 48

Synthesis of 3-acetyl-3 ', 5' -dimethoxybiphenyl

The oven dried Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), 3, 5-dimethoxyphenylchloride (173mg, 1.0mmol), 3-acetylphenylboronic acid (246mg, 1.5mmol) and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon and THF (1mL) was added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl chloride was identified by GC analysis to have been completely consumed. The reaction mixture was then diluted with ethyl acetate (30mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL). The organic layer was washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to yield 232mg (91%) of the title compound.

Example 49

Synthesis of 2-phenylthiophenes

The oven dried Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (2.2mg, 0.01mmol, 1.0 mol%), 2- (di-t-butylphosphino) biphenyl (6.0mg, 0.020mmol, 2.0 mol%), phenylboronic acid (183mg, 1.5mmol) and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (1mL) and 2-bromothiophene (0.097mL, 1.0mmol) were added through a rubber septum. The reaction mixture was stirred at room temperature until the starting aryl bromide was identified by GC analysis to have been completely consumed. The reaction mixture was then diluted with ethyl acetate (30mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL). The organic layer was washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 159mg (99%) of the title compound.

Example 50

Room temperature synthesis of 4-methylbiphenyl using ligand 2, 6-dimethoxyphenyl-di-tert-butylphosphine

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (4.4mg, 0.01mmol, 1 mol%), 2, 6-dimethoxyphenyl-di-tert-butylphosphine (4.2mg, 0.015mmol, 1.5 mol%), phenylboronic acid (183mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (3mL) and 4-chlorotoluene (0.12mL, 1.0mmol) were added through a rubber septum. The spacers were removed, the tube was sealed with a teflon screw cap, and the reaction mixture was stirred at room temperature until GC analysis identified that the starting aryl chloride had been completely consumed. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 164mg (98%) of a glassy solid.

Example 51

Room temperature synthesis of 4-methylbiphenyl utilizing the

ligand

2, 4, 6-trimethoxyphenyl-di-tert-butylphosphine

The oven dried resealable Schlenk tube was evacuated and back-filled with argon and charged with palladium acetate (4.4mg, 0.01mmol, 1 mol%), 2, 4, 6-trimethoxyphenyl-di-tert-butylphosphine (4.7mg, 0.015mmol, 1.5 mol%), phenylboronic acid (183mg, 1.5mmol) and cesium fluoride (456mg, 3.0 mmol). The tube was evacuated and back-filled with argon, and THF (3mL) and 4-chlorotoluene (0.12mL, 1.0mmol) were added through a rubber septum. The spacers were removed, the tube was sealed with a teflon screw cap, and the reaction mixture was stirred at room temperature until GC analysis identified that the starting aryl chloride had been completely consumed. The reaction mixture was then diluted with ether (20mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20mL) and the layers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 165mg (98%) of a glassy solid.

Example 52

Synthesis of 4- (trifluoromethyl) phenylboronic acid

The dried Schlenk tube was charged with magnesium turnings (766mg, 31.5mmol), evacuated and back-filled with argon. To the reaction vessel was added 10mL of diethyl ether followed by 4- (trifluoromethyl) phenyl bromide (4.20mL, 30.0 mmol). The reaction mixture was stirred for 1 hour without external heating, during which time an exotherm occurred and subsequent precipitation. The solution was diluted with ether (10mL) at-78 deg.C and transferred via a catheter to a flask containing a 1: 1 THF/ether (20mL) solution of triisopropyl borate (13.8mL, 60.0 mmol). The resulting reaction mixture was kept at-78 ℃ for 15 minutes and then warmed to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was poured into 2.0M HCl (60 mL). The mixture was transferred to a separatory funnel, extracted with ethyl acetate (60mL), washed with water (60mL) and brine (60 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was dissolved in 2: l hexane/ethyl acetate (90mL) solution and activated carbon was added. The mixture was filtered and the product crystallized upon cooling. The crystals were collected by filtration to give 1.98g (35%) of pale yellow needles.

Example 53

Synthesis of 2-bromo-4' - (trifluoromethyl) biphenyl

The dried Schlenk tube was evacuated and back-filled with argon and charged with tetrakis (triphenylphosphine) palladium (289mg, 0.25mmol, 5.0 mol%), 2-bromoiodobenzene (0.83mL, 6.50mmol), 4- (trifluoromethyl) phenylboronic acid (950mg, 5.0mmol) and sodium carbonate (2.86g, 27.0 mmol). The tube was evacuated and back-filled with argon, and (degassed) dimethoxyethane (45mL), ethanol (2mL) and water (15mL) were added to the tube through a rubber septum. The reaction mixture was heated to 85 ℃ over 32 hours with stirring. The reaction mixture was then diluted with 2: 1 hexane/ethyl acetate (100mL) and poured into a separatory funnel. The mixture was washed with water (80mL) and brine (80 mL). The organic layer was dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 1.01g (67%) of the product.

Example 54

Synthesis of 2- (di-tert-butylphosphino) -4' - (trifluoromethyl) biphenyl

The dried Schlenk tube was evacuated and back-filled with argon and charged with magnesium turnings (90mg, 3.69mmol), 2-bromo-4' - (trifluoromethyl) biphenyl (1.01g, 3.35mmol) and crystals of iodine. The tube was purged with argon for 5 minutes, then THF (6mL) was added through a rubber septum and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and chloroidene (365mg, 3.69mmol) and chloro-di-tert-butylphosphine (0.765mL, 4.03mmol) were added. Heating was continued for a further 14 hours. The reaction mixture was then cooled to room temperature and diluted with ether (40 mL). The suspension was filtered to separate into solids. The solid was partitioned between ethyl acetate (60mL) and 38% ammonium hydroxide (75 mL). The aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH (10mL) to give 131mg (11%) of light yellow needles. A second crop of product was isolated by concentrating the mother liquor and recrystallizing the solid from MeOH (20mL) and water (2mL) to yield 260mg (21%) of product.

Example 55

Synthesis of 2- (di-1-adamantylphosphino) biphenyl

The dried round bottom flask was charged with magnesium turnings (15.3g, 0.63mol) and 1-bromoadamantane (9.0g, 0.041 mol). The flask was evacuated and back-filled with argon twice. To the reaction vessel was added 45mL of diethyl ether and the mixture was slowly refluxed for 15 hours without mechanical stirring. The resulting Grignard reagent solution was drawn into a syringe and added dropwise very slowly to a separate-flame-dried, 2-necked round-bottomed flask equipped with PCl that had been cooled to-40 deg.C₃Reflux condensation of (0.9mL, 10mmol) and 15mL EtherA device. The temperature was monitored during the addition and kept below-25 ℃. The resulting mixture was stirred at-45 ℃ for 30 minutes, then the cold bath was removed and the reaction mixture was slowly warmed to room temperature. After stirring at room temperature for a further 30 minutes, the reaction vessel was placed in a hot oil bath (37 ℃) and slowly refluxed for 22 hours. The mixture was cooled to room temperature and the solution was filtered through a cannula filter. The solvent, as well as some adamantane by-product, was removed in vacuo without exposing the product to air to afford crude di-1-adamantyl chlorophosphine.

An oven dried Schlenk tube was charged with magnesium turnings (240mg, 9.89mmol), 2-bromo-biphenyl (1.55mL, 7.5 mmol). The tube was evacuated and back-filled twice with argon. THF (15mL) was added to the above mixture through a rubber septum and the reaction mixture was heated to gentle reflux for 3 hours. The reaction mixture was then cooled briefly to room temperature to add the chloroidene (930mg, 9.45mmol), followed by a solution of di-1-adamantyl chlorophosphine in 5mL THF. Heating was continued for another 3 hours. The reaction mixture was then cooled to room temperature and diethyl ether (50mL) and pentane (50mL) were added. The resulting suspension was stirred for 10 minutes during which time a large dark brown precipitate formed. The suspension was filtered and the solid was collected on a filter funnel. The solid was partitioned between ethyl acetate-diethyl ether (100mL 1: 1) and 38% ammonium hydroxide-water (100mL 1: 1). The mixture was shaken vigorously several times over 30 minutes. The aqueous layer was washed with ethyl acetate-diethyl ether (100mL 1: 1). The combined organic layers were washed with brine (2 × 50mL), dried over anhydrous magnesium sulfate, decanted, and concentrated in vacuo. The product was crystallized from toluene/methanol to give 450mg (5.8%) of the product as a white solid.

Example 56

Synthesis of 2- (di-tert-butylphosphino) -2' - (isopropyl) biphenyl

The flame-dried Schlenk tube was evacuated and back-filled twice with argon and charged with 2- (bromo) -2' - (isopropyl) biphenyl (1.5g, 5.45mmol) and diethyl ether (15 mL). The reaction mixture was cooled to-78 ℃ using a syringe, passed through a rubberA gel spacer was added dropwise to t-BuLi (6.7mL, 1.7M penate solution). After the addition was complete, the reaction mixture was stirred at-78 ℃ for a further 15 minutes. The cooler was removed and t-Bu was added dropwise₂PCl. After reaching room temperature, the reaction vessel was placed in a hot oil bath (37 ℃) and the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution (10mL) was added, and the resulting mixture was partitioned between ether (100mL) and water (50 mL). The organic layer was dried over a 1: 1 mixture of anhydrous magnesium sulfate and sodium sulfate, decanted, and concentrated in vacuo. The product was crystallized from MeOH togive 601mg (30%) white needles.

Example 57

Synthesis of di-tert-butyl- (o-cyclohexyl) phenylphosphine (3)

The dried Schenk flask was cooled to room temperature under argon purge and charged with 1, 2-dibromobenzene (1.2mL, 10.0mmol), diethyl ether (20mL) and THF (20 mL). Using ethanol/N₂The mixture was cooled to-119 ℃ with stirring in a cold bath. A solution of n-butyllithium in hexane (5.8mL, 1.6M, 9.3mmol) was added slowly dropwise. The mixture was stirred at-119 ℃ for 45 minutes, then cyclohexanone (0.98mL, 9.5mmol) was added to the mixture. The mixture was stirred at-78 ℃ for 30 minutes, warmed to room temperature and stirred for 17 hours. The mixture was quenched with saturated aqueous ammonium chloride (20mL), diluted with ether (50mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (1X 20 mL). The organic layers were combined and washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 1.91g of 1 which was approximately 86% pure by GC analysis. This material was used without further purification.

The round bottom flask was purged with argon and charged with alcohol 1(1.78g, 7.0mmol), dichloromethane (28mL), triethylsilane (1.5mL, 9.1mmol) and trifluoroacetic acid (1.1mL, 14.7 mmol). The mixture was stirred at room temperature for 1.5 hours, then quenched with solid potassium carbonate (about 2 g). The mixture was diluted with diethyl ether (50mL) and transferredTransfer to a separatory funnel. With saturated aqueous NaHCO₃The mixture was washed (50mL), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuoCondensation to give a mixture of 2 and 1- (2-bromophenyl) cyclohexene. The crude was placed in a round bottom flask, which was purged with argon. THF (2mL) was added and the mixture was cooled to 0 ℃ with stirring. To BH₃A solution of THF (7mL, 1M, 7.0mmol) was added dropwise to the mixture. The mixture was stirred at 0 ℃ for 1.5 hours, then warmed to room temperature and stirred for 19 hours. Acetic acid (4mL) was added and the mixture was stirred at room temperature for 6 hours. The mixture was then diluted with ether (50mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (50mL), the layers were separated, and the aqueous phase was extracted with diethyl ether (50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 555mg of 2 which was 93% pure by GC analysis. This material was used without further purification.

The dried Schlenk tube was cooled to room temperature under an argon purge, and charged with magnesium turnings (27mg, 1.1mmol), THF (1mL), and 1, 2-dibromoethane (8. mu.L). The mixture was stirred at room temperature for 10 minutes, then 2(239mg, 1.0mmol) was added in one portion. The mixture was stirred at room temperature for 20 minutes and then heated to 60 ℃ for 15 minutes. The mixture was cooled to room temperature, the septum was removed from the flask, and the chloroidene (I) (104mg, 1.05mmol) was added. The tube was capped with the septum and purged with argon for 1 minute. The tube was charged with di-tert-butylchlorophosphine (0.23mL, 1.2mmol) and an additional amount of THF (1 mL). The mixture was heated to 60 ℃ with stirring for 26 hours. The mixture was cooled to room temperature and filtered, and the solid was washed with diethyl ether/hexanes (50mL, 1/1 v/v). The organic solution was poured into a separatory funnel and washed with ammonium hydroxide solution (3X 50mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel to give 3 as a white solid (141mg) 92% pure by GC analysis. The material was recrystallized from hot methanol to yield 101mg (total yield from 1, 2-dibromobenzene is approximately 3%) of 3 as a white crystalline solid.

Example 58

Preparation of o-di-tert-butylphosphino-o-terphenyl (3)

The dried Schlenk tube was cooled to room temperature under an argon purge, and charged with magnesium turnings (243mg, 11.0mmol), diethyl ether (7mL) and 1, 2-dibromoethane (38. mu.L). The mixture was stirred at room temperature until gas evolution ceased, then a solution of 2-bromobiphenyl (1.7mL, 10.0mmol) in 5mL of diethyl ether was added dropwise. The mixture was stirred at room temperature for 1.75 hours. The solution was then transferred to a separatory funnel containing a solution of triisopropyl borate (4.6mL, 20.0mmol) in THF (20mL) that had been cooled to 0 deg.C. The mixture was stirred at 0 ℃ for 15 minutes, warmed to room temperature and stirred for 21 hours. The reaction was quenched with 1M HCl (40mL) and stirred at room temperature for 10 min. The solution was basified to pH 14 with 6M NaOH and then extracted with ether (1X 10 mL). The organic phase was discarded and the aqueous phase was acidified to pH 2 with 6M HCl. The aqueous phase was extracted with ether (3 × 50mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was recrystallized from ether/pentane at-20 ℃ to give 1.0g (51%) of 1 as a white crystalline solid.

The dried Schenk flask was cooled to room temperature under argon purge and charged with tetrakis (triphenylphosphine) palladium (289mg, 0.25mmol, 5 mol%), sodium carbonate (2.86g, 27mmol) and 1(1.0g, 5.0 mmol). The flask was purged with argon and DME (50mL), ethanol (2mL), water (15mL) and 2-bromoiodobenzene (0.83mL, 6.05mmol) were added through a rubber septum. The mixture was heated to 85 ℃ for 3 days with stirring. The mixture was cooled to room temperature, diluted with ether (100mL) and poured into a separatory funnel. The layers were separated and the organic layer was washed with 1M NaOH (2 × 50mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 1.23g (79%) of 2 as a colorless oil.

The dried Schlenk tube was cooled to room temperature under an argon purge, and charged with magnesium turnings (54mg, 2.2mmol), THF (2mL), and 1, 2-dibromoethane (9. mu.L). The mixture was stirred at room temperature for 15 minutes, then a solution of 2(618mg, 2.0mmol) in 1mL THF was added dropwise. The mixture was stirred at room temperature for 1 hour, the septum was removed from the flask, and the iminoketone (I) chloride (283mg, 2.1mmol) was added. The tube was capped with the septum and purged with argon for 1 minute. The tube was charged with di-tert-butylchlorophosphine (.46mL, 2.4mmol) and an additional amount of THF (1 mL). The mixture was heated to 60 ℃ with stirring for 26 hours. The mixture was cooled to room temperature and filtered, and the solid was washed with diethyl ether/hexanes (50mL, 1/1 v/v). The organic solution was poured into a separatory funnel and washed with ammonium hydroxide solution (3X 50mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was recrystallized from hot methanol to yield 191mg (26%) of3 as a white crystalline solid.

Example 59

Pd-catalyzed carbon-nitrogen bond formation in tert-butanol using (2 ', 4 ', 6 ' -tri-isopropylbiphenyl) dicyclohexylphosphine as a ligand

(2 ', 4 ', 6 ' -tri-isopropylbiphenyl) dicyclohexylphosphine ("ligand 1")

4- (4-butyl-phenylamino) -benzamide

The oven dried resealable Schenk flask was evacuated and back filled with argon. The flask is filled with Pd₂(dba)₃(4.6mg, 0.005mmol, 1.0 mol% Pd), ligand 1(9.4mg, 0.02mmol, 2 mol%), ground K₂CO₃(193mg, 1.4mmol) and 4-amino-benzeneFormamide (163mg, 1.2 mmol). The flask was drained and back-filled with argon (x3) and then capped with a rubber septum. To the flask were added t-BuOH (1.5mL), 4-n-butyl-chlorobenzene (168mg, 1.0mmol) and t-BuOH (0.5 mL). The flask was sealed with a teflon screw cap instead of septum and the mixture was heated to 110 ℃ with stirring until the starting aryl chloride had been consumed by GC analysis (19 hours).The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with EtOAc/hexanes, 8: 2) to give the desired product as a white solid (235mg, 88%).

The same procedure used KOH (1.4mmol, 78mg) instead of potassium carbonate gave the product in 85% yield.

3- (methyl-phenyl-amino) -benzoic acid

The oven dried resealable Schenk flask was evacuated and back filled with argon. The flask is filled with Pd₂(dba)₃(9.2mg, 0.01mmol, 2.0 mol% Pd), ligand 1(19mg, 0.04mmol, 4 mol%), ground KOH (168mg, 3.0mmol), and 3-chlorobenzoic acid (156mg, 1.0mmol) in powder form. The flask was drained and back-filled with argon (x3) and then capped with a rubber septum. To the flask were added t-BuOH (2.0mL), N-methyl-aniline (0.163mL, 1.5mmol) and t-BuOH (0.5 mL). The flask was sealed with a teflon screw cap instead of septum, and the mixture was heated to 100 ℃ with stirring until the starting aryl chloride had been consumed by GC analysis (3 hours, by reaction with MeOH (1-2mL), 2-3 drops of H were added₂SO₄And heated until 0.5mL of a small aliquot of diluted liquid fraction remained, filtered through a small pipette silica gel plug and observed for disappearance of the corresponding methyl ester for GC monitoring). The reaction was cooled to room temperature, diluted with 5% aqueous NaOH and Et₂And (4) extracting. The aqueous layer was cooled to 0 ℃ and acidified to about pH 4 with HCl (12.0M). With Et₂The aqueous layer was extracted with O, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude product (233 mg). The product was purified by recrystallization from hot hexane/chloroform (5: 1) to give a pale yellow solid (191mg, 84%,. gtoreq.95%Purity).

4- (4-butyl-phenylamino) -benzoic acid

Evacuating the oven dried resealable Schenk flaskAnd back-filled with argon. The flask is filled with Pd₂(dba)₃(9.2mg, 0.01mmol, 2.0 mol% Pd), ligand 1(19mg, 0.04mmol, 4 mol%), ground KOH (168mg, 3.0mmol), and 4-amino-benzoic acid (165mg, 1.2mmol) in powder form.The flask was drained and back-filled with argon (x3) and then capped with a rubber septum. To the flask were added t-BuOH (2.0mL), 4-n-butyl-chlorobenzene (168mg, 1.0mmol) and t-BuOH (0.5 mL). The flask was sealed with a teflon screw cap instead of a septum and the mixture was heated to 100 ℃ with stirring until the starting aryl chloride had been consumed by GC analysis (3 hours). The reaction was cooled to room temperature, diluted with 5% aqueous NaOH and Et₂And (4) extracting. The aqueous layer was cooled to 0 ℃ and acidified to about pH 4 with HCl (12.0M). With Et₂The aqueous layer was extracted, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude product (248 mg). The product was purified by recrystallization from hot hexane/chloroform to give dark brown platelets (209mg, 78%).

3- (4-methoxy-phenylamino) -benzamides

The oven dried resealable Schenk flask was evacuated and back filled with argon. The flask is filled with Pd₂(dba)₃(9.2mg, 0.01mmol, 2 mol% Pd), ligand 1(19mg, 0.04mmol, 4 mol%), K₂CO₃(304mg, 2.2mmol), 3-chloro-benzamide (156mg, 1.0mmol) and 4-methoxy-aniline (148mg, 1.2 mmol). The flask was drained and back-filled with argon (x3) and then capped with a rubber septum. To the flask was added t-BuOH (2.5 mL). Replacing spacer with polytetrafluoroethylene screw cap, sealing the flask, and heating the mixture under stirringTo 100 ℃ until the starting aryl chloride has been consumed by GC analysis (20 hours). The reaction was cooled to room temperature, diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (EtOAc/hexane, 8.5: 1.5 elution) to give the desired product, which was recrystallized from ethyl acetate/hexane (14/1) to give white plate crystals (191mg, 79%).

Example 60

General procedure

To a dried resealable Schlenk tube equipped with a stir bar was charged Pd (OAc)₂(2.3mg, 0.01mmol), 2-bis (cyclohexyl) phosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), and phenylboronic acid (3.1mg, 0.025 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. T-butanol (0.5mL) was added via septum with syringe. The reaction mixture was stirred at room temperature for 20 minutes. Under a stream of argon, aryl halide or sulfonate (0.5mmol), amine (0.75mmol) and finely powdered K₂CO₃(173mg, 1.2mmol) was added to a schlenk tube followed by an additional amount of t-butanol (0.5mL) via syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for a specified time and the resulting mixture was cooled to room temperature, filtered through celite using ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column.

4- (3, 5-dimethylphenylamino) benzamide

3, 5-dimethylphenylbenzenesulfonate (131mg, 0.5mmol) and 4-aminobenzamide (102mg, 0.75mmol) were coupled within a reaction time of 6 hours according to the general procedure. Chromatography on a silica gel column with ethyl acetate gave 115mg (96%) of the title compound as a white solid.

2-phenylaminobenzamide

Bromobenzene (55 μ L, 0.5mmol) was coupled with 2-aminobenzamide (102mg, 0.75mmol) according to the general procedure over a reaction time of 15 h. Chromatography on a silica gel column of 1: 1 hexane: ethyl acetate gave 74mg (70%) of the title compound as a white solid.

2- (4-cyanophenylamino) benzamides

Following the general procedure 4-bromobenzonitrile (91mg, 0.5mmol) was coupled with 2-aminobenzamide (102mg, 0.75mmol) over a reaction time of 17 h. Chromatography on a silica gel column of 1: 1 hexane: ethyl acetate afforded 103mg (87%) of the title compound as a pale yellow solid.

N- (4-p-tolylaminophenyl) acetamide

4-chloroacetanilide (85mg, 0.5mmol) was coupled with p-toluidine (80mg, 0.75mmol) at 90 ℃ and 14 h reaction time according to the general procedure. Chromatography on a column of 2: 1 hexanes: ethyl acetate in silica gel gave 118mg (98%) of the title compound as a pink solid.

5- (3, 5-dimethylphenylamino) indole and 1- (3, 5-dimethylphenyl) -5-aminoindole

3, 5-dimethylphenylbenzenesulfonate (131mg, 0.5mmol) and 5-aminoindole (100mg, 0.75mmol) were coupled in the general manner over a reaction time of 4 hours. Chromatography on a column of silica gel 6: 1 hexanes: ethyl acetate afforded 88mg (74%) of 5- (3, 5-dimethylphenylamino) indole as a light brown solid; and 16mg (14%) of 1- (3, 5-dimethylphenyl) -5-aminoindole as a white solid.

4- ((3-aminophenyl) amino) benzoic acid ethyl ester

3-Bromoineaniline (56 μ L, 0.5mmol) was coupled with ethyl 4-aminobenzoate (125mg, 0.75mmol) according to the general procedure at a reaction temperature of 80 ℃ over a reaction time of 17 h. Chromatography on a 4: 1 column of hexane: ethyl acetate on silica gel afforded 55mg (43%) of the title compound as a light brown solid.

N- (4-tert-butylphenyl) -2-pyrrolidone

Following the general procedure 4-tert-butylphenyl benzenesulfonate (145mg, 0.5mmol) was coupled with 2-pyrrolidone (57. mu.L, 0.75mmol) over a reaction time of 21 hours. Chromatography on a silica gel column of 1: 1 hexane: ethyl acetate afforded 103mg (95%) of the title compound as a white solid.

N- (4-tert-butylphenyl) acetamide

Following the general procedure 4-tert-butylphenyl benzenesulfonate (145mg, 0.5mmol) and acetamide (45mg, 0.75mmol) were coupled over a reaction time of 21 h. Chromatography on a silica gel column of 1: 1 hexane: ethyl acetate afforded 84mg (88%) of the title compound as a white solid.

N- (3, 5-dimethylphenyl) -N-methylformamide

3, 5-dimethylphenylbenzenesulfonate (131mg, 0.5mmol) and N-methylformamide (45mg, 0.75mmol) were coupled in the general manner over a reaction time of 20 h. Chromatography on a 4: 1 hexane: ethyl acetate column on silica gel afforded 76mg (93%) of the title compound as a colorless oil.

N- (3, 4-methylenedioxyphenyl) carbamic acid tert-butyl ester

According to the general procedure, in addition to 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (19.0mg, 0.040mmol) being used, 3, 4-methylenedioxyphenyltosylate (146mg, 0.5mmol) was coupled with tert-butyl carbamate (90mg, 0.75mmol) over a reaction time of 24 h. Chromatography on a 10: 1 hexane: ethyl acetate column of silica gel afforded 101mg (85%) of the title compound as a white solid.

N- (1-naphthyl) benzamide

1-naphthyl tosylate (149mg, 0.5mmol) was coupled with benzamide (90mg, 0.75mmol) over a reaction time of 20 h according to the general procedure. Chromatography on a 4: 1 hexane: ethyl acetate column of silica gel afforded 117mg (95%) of the title compound as a white solid.

Example 61

3-morpholine-acetanilide

To a dried resealable Schlenk tube equipped with a stir bar was charged Pd (OAc)₂(2.3mg, 0.01mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 3- (N-acetyl) phenyl tosylate (153mg, 0.5mmol) and K ground to a fine powder₂CO₃(173mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. Morpholine (66. mu.L, 0.75mmol) and tert-butanol (1mL) were added via a septum with a syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 20 hours, cooled to room temperature, filtered through celite using ethyl acetate. Silica gel column chromatography on ethyl acetate afforded 110mg (100%) of the title compound as a white solid.

Example 62

N- (4-hexylaminophenyl) acetamide

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg，0.005mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 4-bromoacetanilide (107mg, 0.5mmol) and sodium tert-butoxide (120mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. N-hexylamine (100. mu.L, 0.75mmol) and t-butanol (1mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 3 hours, cooled to room temperature and quenched with water. Extraction with ethyl acetate three times, followed by silica gel column chromatography with 1: 1 hexane: ethyl acetate gave 95mg (81%) of the title compound as a white solid.

Example 63

α - (4-tert-butylphenyl) cycloheptanone

To a dried resealable Schlenk tube equipped with a stir bar was charged Pd (OAc)₂(2.3mg, 0.01mmol), 2-bis-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 4-tert-butylphenyl benzenesulfonate (145mg, 0.5mmol), and Cs₂CO₃(408mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. Cyclohexanone (90. mu.L, 0.75mmol), toluene (1mL) and t-butanol (0.2mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 21 hours, cooled to room temperature and filtered through celite using ethyl acetate. Silica gel column chromatography with 30: 1 hexane: ethyl acetate afforded 104mg (85%) of the title compound as a white solid.

Example 64

α - (4-tert-butylphenyl) malonic acid diethyl ester

To a dried resealable Schlenk tube equipped with a stir bar was charged Pd (OAc)₂(2.3mg, 0.01mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 4-tert-butylphenyl benzenesulfonate (145mg, 0.5mmol) and Cs₂CO₃(408mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. Diethyl malonate (115. mu.L, 0.75mmol) and toluene (1mL) were added via septum with a syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 18 hours, cooled to room temperature and filtered through celite using ethyl acetate. Silica gel column chromatography 10: 1 hexanes: ethyl acetate afforded 131mg (90%) of the title compound as a colorless oil.

Example 65

α -phenyl- α - (4-tert-butylphenyl) acetic acid ethyl ester

To a dried resealable Schlenk tube equipped with a stir bar was charged Pd (OAc)₂(2.3mg, 0.01mmol), 2-bis-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 4-tert-butylphenyl benzenesulfonate (145mg, 0.5mmol), and Cs₂CO₃(408mg, 1.2 mmol.) the tube was capped with a rubber septum, evacuated and back-filled with argon, α -phenylacetic acid ethyl ester (120. mu.L, 0.75mmol), toluene (1mL) and t-butanol (0.2mL) were added through the septum with a syringe, the septum was replaced with a Teflon screw cap, the schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. the reactions were mixedThe mixture was stirred for 20 hours, cooled to room temperature and filtered through celite using ethyl acetate. Column chromatography on silica gel with 4: 1 hexane: dichloromethane afforded 130mg (88%) of the title compound as a colorless oil.

Example 66

Suzuki cross-coupling reaction of aryltosylate and arylboronic acid

General procedure

Pd (OAc)₂(1-2 mol%), phosphine ligand (2-5 mol%), aryl toluene sulfonic acidThe ester (1 eq), arylboronic acid (2 eq) and base (3 eq) were added to a Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and back-filled with argon three times. THF (1mL) was added via syringe under nitrogen or argon atmosphere. The tube was sealed with teflon screw caps and heated in an oil bath to a specific temperature for a specific time, as per GC, TLC and/or gross¹H NMR showed the reaction was complete, the reaction tube was cooled to room temperature. The reaction was then quenched with 1mL 1M aqueous HCl and diluted with 5mL EtOAc. The organic layer was separated and the aqueous layer was washed with EtOAc (2X 5 mL). For pyridine and quinoline compounds, the reaction was quenched with 1mL of water and the aqueous layer was washed repeatedly with EtOAc until all the product was extracted. Via MeSO₄The combined organic layers were dried. Adding MeSO₄After filtration, the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane: EtOAc to afford the product.

The specific schemes for most of the general methods are listed in tables 13-18.

Example 67

5- (4-n-butylphenyl-amino) -indole and 1- (4-n-butylphenyl) -5-aminoindole

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylideneBenzene (11.9mg, 0.025mmol), 5-aminoindole (100mg, 0.75mmol) and K₂CO₃(173mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. 4-n-butylchlorobenzene (85mg, 0.5mmol) and tert-butanol (1mL) were added via a septum with a syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 3 hours, cooled to room temperature and filtered through celite using ethyl acetate. The filtrate was concentrated under reduced pressure. Silica gel column chromatography with 4: 1 hexane: ethyl acetate afforded 106mg (80%) of 5- (4-n-butylphenyl amino) indole asLight brown solid. This gave 1- (4-n-butylphenyl) -5-aminoindole in a GC yield of 10%.

Example 68

4- ((3-aminophenyl) amino) benzoic acid ethyl ester

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (17.0mg, 0.04mmol), ethyl 4-aminobenzoate (125mg, 0.75mmol) and K₂CO₃(173mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. 3-Bromoianiline (56 μ L, 0.5mmol) and t-butanol (1mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 80 ℃. The reaction mixture was stirred for 11 hours, cooled to room temperature and filtered through celite using ethyl acetate. The filtrate was concentrated under reduced pressure. Column chromatography on silica gel with 4: 1 hexane: ethyl acetate afforded 103mg (80%) of the title compound as a pale yellow oil.

Example 69

2- (2-methylphenylamino) benzamide and 2-amino-N- (2-methylphenyl) benzamide

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (19.0mg, 0.04mmol), 2-aminobenzamide (170mg, 1.25mmol) and K₂CO₃(173mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. 2-bromotoluene (60 μ L, 0.5mmol) and t-butanol (1mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. Mixing the reaction mixtureStir 17 hours, cool to room temperature and filter through celite using ethyl acetate. The filtrate was concentrated under reduced pressure. Silica gel column chromatography with 4: 1 hexane: ethyl acetate afforded 98mg (87%) of 2- (2-methylphenylamino) benzamide and 11mg (10%) of 2-amino-N- (2-methylphenyl) benzamide as a white solid.

Example 70

N- (2-p-tolylaminophenyl) acetamide

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (19.0mg, 0.04mmol), 2-bromoacetanilide (107mg, 0.5mmol), p-toluidine (80mg, 0.75mmol) and K₂CO₃(265mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. tert-Butanol (1) was added via septum by syringemL). The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 18 hours, cooled to room temperature and filtered through celite using ethyl acetate. The filtrate was concentrated under reduced pressure. Silica gel column chromatography with 1: 1 hexane: ethyl acetate afforded 107mg (89%) of the title compound as a brown solid.

Example 71

N- (3-dibutylaminophenyl) acetamide

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (11.9mg, 0.025mmol), 3-chloroacetanilide (85mg, 0.5mmol) and sodium tert-butoxide (120mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. Di-n-butylamine (126 μ L, 0.75 m) was added via septum by syringemol) and tert-butanol (1 mL). The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 90 ℃. The reaction mixture was stirred for 18 hours, cooled to room temperature and quenched with water. Extraction with ethyl acetate three times, followed by column chromatography on silica gel with 4: 1 hexane: ethyl acetate gave 106mg (81%) of the title compound as a pale yellow oil.

Example 72

2-phenylaminobenzamide and 2-amino-N-phenylbenzamide using tert-amyl alcohol as solvent

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol), 2-di-cyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (19.0mg, 0.04mmol), 2-aminobenzamide (102mg, 0.75mmol) andK₂CO₃(173mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. Bromobenzene (55. mu.L, 0.5mmol) and tert-amyl alcohol (1mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 15 hours and cooled to room temperature. GC analysis showed complete conversion of bromobenzene. This gave a 65% GC yield of 2-phenylanthranilamide and a 10% GC yield of 2-amino-N-phenylbenzamide.

Example 73

Using PtBu₃N- (4-hexylaminophenyl) acetamide as ligand

The dried resealable Schlenk tube equipped with a stir bar was charged with Pd₂(dba)₃(4.6mg, 0.005mmol) and 4-bromoacetanilide (107mg, 0.5 mmol). The tube was capped with a rubber septum, evacuated and back filled with argon. The tube was capped with a rubber septum, evacuated and back filled with argon. Using teflon screw cap instead of spacerThe tube was placed in an oven. The tube was rinsed with tri-tert-butylphosphine (5.1mg, 0.025mmol) and sodium tert-butoxide (120mg, 1.25mmol) and sealed with a teflon screw cap. Under a flow of argon, the tube was taken out of the vacuum glove box (glovebox) and replaced with a rubber septum instead of a teflon screw cap. N-hexylamine (100. mu.L, 0.75mmol) and t-butanol (1mL) were added via septum with syringe. The spacers are replaced by teflon screw caps. The schlenk tube was sealed and placed in an oil bath preheated at 110 ℃. The reaction mixture was stirred for 3 hours, cooled to room temperature and quenched with water. The aqueous layer was extracted three times with ethyl acetate. GC analysis of the organics showed the title compound to be obtained in 25% GC yield.

Example 74

Amination catalyzed in water using Pd-complexes of aryl chlorides and potassium hydroxide

A resealable Schenk flask was charged with palladium complex (0.01mmol) and KOH (86mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (1mmol), morpholine (1.2mmol) and deionized, degassed water (0.5mL) were added. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 18 hours. When all starting material was consumed by GC, the mixture was cooled to room temperature and then diluted with ether (40 mL). The resulting suspension was transferred to a separatory funnel and washed with water (10 mL). Separating the organic layer with MgSO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

Example 75

The oven dried resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol) and KOH (84mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol), aniline (109 μ L, 1.2mmol), dodecane (15mg) as an internal standard, and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 14 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 76

An oven dried resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol), KOH (86mg, 1.5mmol) and indole (140mg, 1.2 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol) and t-water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 17 hours. When all starting material was consumed by GC, the mixture was cooled to room temperature and then diluted with ether (40 mL). The resulting suspension was transferred to a separatory funnel and washed with water (10 mL). Separating the organic layer with MgSO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

Example 77

A resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol) and KOH (84mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 3-trifluoromethylchlorobenzene (163. mu.L, 1mmol), aniline (109. mu.L, 1.2mmol), dodecane (15mg) as an internal standard, and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 3 hours. The reaction was thereafter cooled to room temperature and conversion and yield were determined by gas chromatography using dodecane as an internal standard.

Chromatography

Example 78

A resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol), 4-chloronitrobenzene (158mg, 1mmol) and KOH (84mg, 1.5 mmol). The flask was evacuated and back-filled with argon, to which was then added aniline (109 μ L, 1.2mmol), dodecane (15mg) as an internal standard, and water (0.5 mL). The flask was sealed with a teflon screw cap and the mixture was stirred at 50 ℃ for 3 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 79

A resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol) and KOH (84mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol), morpholine (104 μ L, 1.2mmol), dodecane (15mg) as an internal standard and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 2 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 80

A resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol), cetyltrimethylammonium bromide (36.4mg, 0.1mmol) and KOH (84mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol), morpholine (104 μ L, 1.2mmol), dodecane (15mg) as an internal standard and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 2 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 81

Amination catalyzed in water using Pd-complexes of aryl chloride and potassium carbonate

A resealable Schenk flask was charged with palladium complex (0.01mmol) and K₂CO₃(207mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then added4-n-butylchlorobenzene (1mmol), morpholine (1.2mmol) and degassed, deionized water (0.5mL) were added. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 18 hours. When all starting material was consumed by GC, the mixture was cooled to room temperature and then diluted with ether (40 mL). The resulting suspension was transferred to a separatory funnel and washed with water (10 mL). Separating the organic layer with MgSO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

Example 82

Amination catalyzed in water using Pd-complexes of aryl chlorides and sodium hydroxide

An oven dried resealable Schenk flask was charged with palladium complex (8.3mg, 0.01mmol) and NaOH (60mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol), morpholine (104 μ L, 1.2mmol), dodecane (15mg) as an internal standard and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 17 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 83

The oven dried resealable Schenk flask was charged with palladium complex (4.6mg, 0.01mmol) and NaOH (60mg, 1.5 mmol). The flask was evacuated and back-filled with argon, then 4-n-butylchlorobenzene (170 μ L, 1mmol), morpholine (104 μ L, 1.2mmol), dodecane (15mg) as an internal standard and water (0.5mL) were added thereto. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 17 hours. The mixture was thereafter cooled to room temperature and the conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 84

Pd with aryl chloride and potassium hydroxide in water₂(dba)₃Catalytic amination

The resealable Schenk flask was evacuated and back filled with argon. The flask was charged with Pd₂(dba)₃(4.6mg, 0.005mmol, 1 mol% Pd), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (9.5mg, 0.02mmol, 2 mol%) and powdered KOH (78mg, 1.4 mmol). The flask was evacuated and back filled with argon (3 ×) and capped with a rubber septum. 2-chloro-p-xylene (0.134mL, 1.0mmol), n-hexyl-amine (0.58mL, 1.2mmol) and degassed water (0.5mL) were added via the septum. The polytetrafluoroethylene screw cap is used for replacing the spacerThe flask was sealed and the mixture was heated to 110 ℃ with stirring. After 2 hours, 54% of the aryl halide had been consumed and there was no further conversion by reheating (50% GC yield).

Example 85

The resealable Schlenk flask was evacuated and back filled with argon. The flask was charged with Pd₂(dba)₃(4.6mg, 0.005mmol, 1 mol% Pd), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -tri-isopropylbiphenyl (9.5mg, 0.02mmol, 2 mol%) and powdered KOH (78mg, 1.4 mmol). The flask was evacuated and back filled with argon (3 ×) and capped with a rubber septum. 3-chloro-pyridine (0.095mL, 1.0mmol), aniline (0.109mL, 1.2mmol) and degassed water (0.5mL) were added via the septum. The flask was sealed with a teflon screw cap instead of septum and the mixture was heated to 110 ℃ with stirring until the starting aryl halide had been consumed by GC analysis (6 hours). After the aryl halide was completely consumed, the reaction was cooled to room temperature, diluted with ethyl acetate, filtered through celite and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (eluted with 70% ethyl acetate in hexanes) to give the desired product as a white solid (162mg, 95%).

Example 86

Pd (II) -catalyzed amination of acetic acid using aryl chloride and potassium hydroxide in water

A resealable Schlenk flask was charged with palladium acetate (2.2mg, 0.01mmol), ligand (9.5mg, 0.02mmol) and KOH (86mg, 1.5 mmol). The flask was evacuated and back filled with argon. 4-n-butylchlorobenzene (170mL, 1mmol), morpholine (104mL, 1.2mmol), dodecane (as an internal standard; 15mg) and water (0.5mL) were then added. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 16 hours. The reaction was cooled to room temperature and conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 87

Pd (II) -catalyzed amination of acetic acid using aryl chloride and sodium hydroxide in water

A resealable Schlenk flask was charged with palladium acetate (2.2mg, 0.01mmol), ligand (9.5mg, 0.02mmol) and NaOH (60mg, 1.5 mmol). The flask was evacuated and back filled with argon. 4-n-butylchlorobenzene (170mL, 1mmol), morpholine (104mL, 1.2mmol), dodecane (as an internal standard; 15mg), and water (0.5mL) were then added. The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 16 hours. The reaction was cooled to room temperature and conversion and yield were determined by gas chromatography using dodecane as internal standard.

Example 88

Pd (II) -catalyzed amination of acetic acid using aryl bromides and potassium hydroxide in water using different ligands

Ligands used

4-toluidine (129mg, 1.2mmol), Pd (OAc)₂(2.3mg, 0.01mmol), ligand (0.025mmol) and KOH (78mg, 1.4mmol) were charged into a Schlenk tube. The tube was evacuated and back-filled twice with argon; then, 4-tert-butylbromobenzene (213mg, 0.177mL, 1mmol) and water (0.5mL) were added. The resulting mixture was refluxed at 110 ℃ for 12 hours. The product was analyzed by GC analysis (with dodecane as internal standard).

The reaction was carried out using BINAP as a ligand (15 mg). GC conversion: 67%, GC yield 65%.

The reaction was carried out using tri-tert-butylphosphine as a ligand, and the instantly produced tri-tert-butylphosphonium tetrafluoroborate (8mg) was reacted with KOH: GC conversion 99% and GC yield 97%.

The reaction was carried out using ligand 1(12mg) with 99% GC conversion and 98% GC yield.

The reaction was carried out using 1, 3-bis (2, 6-di-i-propylphenyl) -4, 5-dihydroimidazolium tetrafluoroborate with a GC conversion of 10% and a GC yield of 5%.

Example 89

Pd (II) -acetate catalyzed amination in water using aryl bromides and tributylamine, using different ligands

Ligands used

4-toluidine (129mg, 1.2mmol), Pd (OAc)₂(2.3mg, 0.01mmol) and ligand (0.025mmol) were charged to a Schlenk tube. The tube was evacuated and back-filled twice with argon; then, 4-tert-butylbromobenzene (213mg, 0.177mL, 1mmol), tributylamine (0.332mL mg, 1.4mmol), and water (0.5mL) were added. The resulting mixture was refluxed at 110 ℃ for 3 hours. The product was analyzed by GC analysis (using dodecane as internal standard).

The reaction was carried out using BINAP as a ligand (15 mg). GC conversion: 1%, GC yield was less than 1%.

The reaction was carried out using tri-tert-butylphosphonium tetrafluoroborate as ligand (8mg) with 2% GC conversion and 1% GC yield.

The reaction was carried out using ligand 1(12mg) with 3% GC conversion and 2% GC yield.

The reaction was carried out using 1, 3-bis (2, 6-di-i-propylphenyl) -4, 5-dihydroimidazolium tetrafluoroborate with a GC conversion of less than 1% and a GC yield of less than 1%.

Example 90

Pd (II) -catalyzed amination of acetic acid using aryl bromide and potassium hydroxide in water, using different ligands, without phenylboronic acid

Ligands used

4-toluidine (129mg, 1.2mmol), Pd (OAc)₂(2.3mg, 0.01mmol), ligand (0.025mmol) and KOH (78mg, 1.4mmol) were charged into a Schlenk tube. The tube was evacuated and back-filled twice with argon; then, 4-tert-butylbromobenzene (213mg, 0.177mL, 1mmol) and water (0.5mL) were added. The resulting mixture was refluxed at 110 ℃ for 12 hours. The product was analyzed by GC analysis (using dodecane as internal standard).

The reaction was carried out using tri-tert-butylphosphonium tetrafluoroborate as ligand (8mg) with 99% GC conversion and 85% GC yield.

Example 91

Pd (II) -acetate catalyzed amination in water using aryl bromides and sodium hydroxide, using different ligands

Ligands used

4-toluidine (129mg, 1.2mmol), Pd (OAc)₂(2.3mg, 0.01mmol), ligand (0.025mmol) and NaOH (78mg, 1.4mmol) were charged into a Schlenk tube. The tube was evacuated and back-filled twice with argon; then, 4-tert-butylbromobenzene (213mg, 0.177mL, 1mmol) and water (0.5mL) were added. The resulting mixture was refluxed at 110 ℃ for 3 hours. The product was analyzed by GC analysis (using dodecane as internal standard).

The reaction was carried out using BINAP as ligand (15mg) with 4% GC conversion and 2% GC yield.

The reaction was carried out using tri-tert-butylphosphonium tetrafluoroborate as ligand (8mg) with 99% GC conversion and 97% GC yield.

The reaction was carried out using 1, 3-bis (2, 6-di-isopropylphenyl) -4, 5-dihydroimidazolium tetrafluoroborate with a GC conversion of 1% and a GC yield of 1%.

Example 92

Pd-complex-catalyzed amination in tert-butanol using aryl chloride and potassium carbonate

The oven-dried resealable Schlenk tube was charged with palladium complex (0.01mmol) and K₂CO₃(207mg, 1.5 mmol). The tube was evacuated and back-filled with argon, to which was then added 4-n-butylchlorobenzene (1mmol), morpholine (1.2mmol) and tert-butanol (1 mL). The flask was sealed with a teflon screw cap and the mixture was stirred at 110 ℃ for 18 hours. When all starting material was consumed as identified by GC analysis, the mixture was cooled to room temperature and then diluted with ether (40 mL). The resulting suspension was transferred to a separatory funnel and washed with water (10 mL). Separating the organic layer with MgSO₄Dried and concentrated under vacuum. The crude material was purifiedby flash chromatography on silica gel.

Example 93

Pd-complex-catalyzed amination in tert-butanol using aryl chlorides and potassium hydroxide

The oven-dried resealable Schlenk tube was charged with palladium complex (0.01mmol) and KOH (86mg, 1.5 mmol). The tube was evacuated and back-filled with argon, to which was then added 4-n-butylchlorobenzene (1mmol), morpholine (1.2mmol) and tert-butanol (1 mL). The flask was sealed with a teflon screw cap and the mixture was refluxed at 110 ℃ for 18 hours. When all starting material was consumed as identified by GC analysis, the mixture was cooled to room temperature and then diluted with ether (40 mL). The resulting suspension was transferred to a separatory funnel and washed with water (10 mL). Separating the organic layer with MgSO₄Dried and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel.

INCORPORATION BY REFERENCE

All patents and publications mentioned herein are incorporated by reference.

Equivalent object

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A ligand represented by structure I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

2. A ligand according to claim 1, wherein R independently represents at each occurrence alkyl, cycloalkyl or aryl; at least two kinds of R exist₂Examples of (1); for each case, R₂Independently selected from alkyl and cycloalkyl.

3. A ligand represented by structure II:

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

4. The ligand of claim 3, wherein R₁Is absent, and R₂Is absent.

5. A ligand according to claim 3, wherein R independently represents at each occurrence alkyl or cycloalkyl.

6. A ligand according to claim 3, wherein R independently represents at each occurrence ethyl, cyclohexyl, cyclopropyl, isopropyl or tert-butyl.

7. A ligand according to claim 3, wherein R independently represents cyclohexyl at each occurrence.

8. A ligand according to claim 3, wherein R' independently represents alkyl at each occurrence.

9. A ligand according to claim 3, wherein R' independently represents at each occurrence isopropyl.

10. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; and for each occurrence, R independently represents alkyl or cycloalkyl.

11. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl.

12. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl.

13. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents alkyl or cycloalkyl; and for each occurrence, R' independently represents an alkyl group.

14. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, or tert-butyl; and for each occurrence, R' independently represents an alkyl group.

15. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl; and for each occurrence, R' independently represents an alkyl group.

16. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; to pairIn each case, R independently represents alkyl or cycloalkyl; and for each occurrence, R' independently represents isopropyl.

17. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents ethyl, cyclohexyl, cyclopropyl, isopropyl, ortert-butyl; and for each occurrence, R' independently represents isopropyl.

18. The ligand of claim 3, wherein R₁Is absent; r₂Is absent; for each occurrence, R independently represents cyclohexyl; and for each occurrence, R' independently represents isopropyl.

19. A method represented by scheme 1:

scheme 1

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

r 'and R' taken together may form an optionally substituted ring consisting of 3 to 10 main chain atoms; said ring optionally containing one or more heteroatoms other than the nitrogen to which R 'and R' are attached;

r 'and/or R' may be covalently linked to Z;

the transition metal is selected from group 10 metals;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

When present, R for each case₁And R₂Independently selected from alkyl, cycloalkylHalogen, -SiR₃And- (CH)₂)_m-R₈₀；

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

20. The method of claim 19, wherein the transition metal is palladium.

21. The method of claim 19, wherein Z represents optionally substituted aryl.

22. A method represented by scheme 2:

scheme 2

Wherein

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

z and Ar' may be covalently linked;

the transition metal is selected from group 10 metals;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

23. The method of claim 22, wherein the transition metal is palladium.

24. The method of claim 22, wherein Z represents optionally substituted aryl.

25. The method of claim 22, wherein X is-OS (O)₂And (4) an aryl group.

26. The method of claim 22, wherein X is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group.

27. The method of claim 22, wherein X is-OS (O)₂Tolyl radicals.

28. The method of claim 22, wherein the base is selected from the group consisting of fluoride, carbonate, and phosphate.

29. The method of claim 22, wherein the base is cesium fluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

30. The method of claim 22, wherein the transition metal is palladium; and X is-OS (O)₂And (4) an aryl group.

31. The method of claim 22, wherein the transition metal is palladium; and X is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group.

32. The method of claim 22, wherein the transition metal is palladium; and X is-OS (O)₂Tolyl radicals.

33. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂An aryl group; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

34. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group; to be provided withAnd the base is selected from the group consisting of fluoride, carbonate and phosphate.

35. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂Tolyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

36. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂An aryl group; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

37. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂Tolyl radical or-OS (O)₂A phenyl group; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

38. The method of claim 22, wherein the transition metal is palladium; x is-OS (O)₂Tolyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

39. A method represented by scheme 3:

scheme 3

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

one of Z and R, R' and R "may be covalently linked;

the transition metal is selected from group 10 metals;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

The A and A' rings of the biphenyl center may independently be unsubstituted orEach of which is represented by R₁And R₂Substitution, any maximum number of substitutions is defined by the rules of stability and valency.

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

40. The method of claim 39, wherein the transition metal is palladium.

41. The method of claim 39, wherein Z represents optionally substituted aryl.

42. A method represented by scheme 4:

scheme 4

Wherein

ar' is selected from optionally substituted aromatic moieties;

z and Ar' may be covalently linked;

the ligand is selected from:

a compound represented by I:

wherein

The A and A' rings of the biphenyl center may be independently unsubstituted or each independently represented by R₁And R₂Substitutions, any maximum number of substitutions being defined by the rules of stability and valency;

R₈₀Represents unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle orpolycycle;

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

43. The method of claim 42, wherein Z represents optionally substituted aryl.

44. The method of claim 42, wherein Ar "is tolyl or phenyl.

45. The method of claim 42, wherein Ar "is tolyl.

46. The method of claim 42, wherein the base is selected from the groupconsisting of fluoride, carbonate, and phosphate.

47. The method of claim 42, wherein the base is cesium fluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

48. The method of claim 42, wherein Ar "is tolyl or phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

49. The method of claim 42, wherein Ar "is tolyl or phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

50. The method of claim 42, wherein Ar "is tolyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

51. The method of claim 42, wherein Ar "is tolyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

52. A method represented by scheme 5:

scheme 5

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

ar' is selected from optionally substituted aromatic moieties;

one of Z and R, R' and R "may be covalently linked;

the ligand is selected from:

a compound represented by I:

wherein

R₈₀Represents unsubstituted or substituted arylAryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle;

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

53. The method of claim 52, wherein Z represents optionally substituted aryl.

54. The method of claim 52, wherein Ar "is tolyl or phenyl.

55. The method of claim 52, wherein Ar "is phenyl.

56. The method of claim 52, wherein the base is selected from the group consisting of fluoride, carbonate, and phosphate.

57. The method of claim 52, wherein said base is cesium fluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

58. The method of claim 52, wherein Ar "is tolyl or phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

59. The method of claim 52, wherein Ar "is tolyl or phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

60. The method of claim 52, wherein Ar "is phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

61. The method of claim 52, wherein Ar "is phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

62. A method represented by scheme 6:

scheme 6

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

r 'and R' taken together may form an optionally substituted ring containing 3 to 10 backbone atoms; said ring optionally containing one or more heteroatoms other than the nitrogen atom to which R 'and R' are attached;

r 'and/or R' may be covalently linked to Z;

the solvent is water;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

63. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides.

64. The method of claim 62, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide.

65. The method of claim 62, wherein the base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide.

66. The method of claim 62, wherein X is Cl, Br, or I.

67. The method of claim 62, wherein X is Cl or Br.

68. The method of claim 62, wherein X is Cl.

69. The method of claim 62, wherein Z represents optionally substituted aryl.

70. The method of claim 62, wherein Z is optionally substituted phenyl.

71. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; and X is Cl, Br or I.

72. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; x is Cl, Br or I; and Z is optionally substituted phenyl.

73. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; x is Cl or Br.

74. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; x is Cl or Br; and Z is optionally substituted phenyl.

75. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; and X is Cl.

76. The method of claim 62, wherein the base is selected from the group consisting of carbonates and hydroxides; x is Cl; and Z is optionally substituted phenyl.

77. The process of claim 62, wherein the base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl, Br or I; and Z is optionally substituted phenyl.

78. The process of claim 62, wherein the base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl or Br; and Z is optionally substituted phenyl.

79. The process of claim 62, wherein the base is selected from the group consisting of potassium carbonate, sodium hydroxide, and potassium hydroxide; x is Cl; and Z is optionally substituted phenyl.

80. A method represented by scheme 7:

scheme 7

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

x is selected from Cl, Br, I, -OS (O)₂Alkyl and-OS (O)₂An aryl group;

r 'and/or R' may be covalently linked to Z;

the solvent comprises greater than 50% by volume of a hydroxylic solvent;

the ligand is selected from:

a compound represented by I:

wherein

R₈₀Is unsubstituted or takenSubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle;

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

81. The method of claim 80, wherein the hydroxylic solvent is a lower alkyl alcohol.

82. The method of claim 80, wherein the hydroxylic solvent is t-butanol.

83. The method of claim 80, wherein the solvent consists essentially of the hydroxylic solvent.

84. The method of claim 80, wherein the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides.

85. The method of claim 80, wherein the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium t-butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

86. The method of claim 80, wherein X is Cl or Br.

87. The method of claim 80, wherein Z represents optionally substituted aryl.

88. The method of claim 80, wherein Z is optionally substituted phenyl.

89. The method of claim 80 wherein the hydroxylic solvent is a lower alkyl alcohol; and the solvent consists essentially of the hydroxylic solvent.

90. The method of claim 80, wherein the hydroxylic solvent is t-butanol; and the solvent consists essentially of the hydroxylic solvent.

91. The method of claim 80 wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides.

92. The method of claim 80 wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides; and X is Cl or Br.

93. The method of claim 80 wherein the hydroxylic solvent is a lower alkyl alcohol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of alkoxides, carbonates, phosphates, and hydroxides; x is Cl or Br, and Z is optionally substituted phenyl.

94. The method of claim 80, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; and the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

95. The method of claim80, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and X is Cl or Br.

96. The method of claim 80, wherein the hydroxylic solvent is t-butanol; the solvent consists essentially of the hydroxylic solvent; the base is selected from the group consisting of sodium phosphate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; x is Cl or Br; and Z is optionally substituted phenyl.

97. A method represented by scheme 8:

scheme 8

Wherein

Z is selected from optionally substituted aryl, heteroaryl and alkenyl;

ar' is selected from optionally substituted aromatic moieties;

r is selected from optionally substituted alkyl and aralkyl;

for each occurrence, R' is independently selected from alkyl and heteroalkyl; the carbon-boron bond of the alkyl and heteroalkyl groups is inert under reaction conditions; b (R')₂Together may represent 9-borabicyclo [3.3.1]Nonyl radical.

Z and R may be covalently linked;

the ligand is selected from:

a compound represented by I:

wherein

m is independently for each occurrence an integer in the range of 0 to 8; and

wherein

For each case, R₈₀Independently represents cycloalkyl or aryl;

m is independently for each occurrence an integer in the range of 0 to 8; and

when chiral, the ligand is a mixture of enantiomers or a single enantiomer.

98. The method of claim 97, wherein Z represents optionally substituted aryl.

99. The method of claim 97, wherein Ar "is tolyl or phenyl.

100. The method of claim 97, wherein the base is selected from the group consisting of fluoride, carbonate, and phosphate.

101. The method of claim 97, wherein said base is cesium fluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

102. The method of claim 97, wherein B (R')₂Together represent 9-borabicyclo [3.3.1]Nonyl radical.

103. The method of claim 97, wherein Ar "is tolyl or phenyl; and the base is selected from the group consisting of fluoride, carbonate and phosphate.

104. The method of claim 97, wherein Ar "is tolyl or phenyl; and the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate.

105. The method of claim 97, wherein Ar "is tolyl or phenyl; the base is selected from fluoride, carbonate and phosphate; and B (R')₂Together represent 9-borabicyclo [3.3.1]Nonyl radical.

106. The method ofThe process of claim 97, wherein Ar "is tolyl or phenyl; the base is cesium fluoride, potassium fluoride, cesium carbonate or potassium phosphate; and B (R')₂Together represent 9-borabicyclo [3.3.1]Nonyl radical.